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Biomedical subjects

J M Rowe

Publications and source records attributed to J M Rowe.

At least 37 records · Page 2Linked to original sources
PubMed2001

Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters.

Between September 1993 and December 1993, during extensive hospital construction and indoor renovation, a nosocomial outbreak of invasive pulmonary aspergillosis occurred in acute leukemia patients treated in a regular ward that has only natural ventilation. The observed infection rate was 50%. Chemoprophylaxis with intravenous continuous low-dose amphotericin B was then instituted as a preventive measure. During the next 18 months invasive pulmonary aspergillosis developed in 43% of acute leukemia patients. After that period a new hematology ward was opened with an air filtration system through high-efficiency particulate air filtration (HEPA) filters, and a bone marrow transplantation program was started on the hematology service. During the following three years, none of the acute leukemia or bone marrow transplantation patients who were hospitalized exclusively in the hematology ward developed invasive pulmonary aspergillosis, although 29% of acute leukemia patients who were housed in a regular ward, because of shortage of space in the new facility, still contracted invasive pulmonary aspergillosis. Overall, 31 patients were diagnosed with invasive pulmonary aspergillosis during almost five years: 74% of patients recovered from invasive pulmonary aspergillosis, and 42% are long-term survivors; 26% of patients died of resistant leukemia with aspergillosis, but no one died of invasive pulmonary aspergillosis alone. In conclusion, during an on-going construction period, an extremely high incidence rate of invasive pulmonary aspergillosis in acute leukemia patients undergoing intensive chemotherapy was observed. Institution of low-dose intravenous amphotericin B prophylaxis marginally reduced the incidence rate of invasive pulmonary aspergillosis. Keeping patients in a special ward with air filtration through a HEPA system eliminated invasive pulmonary aspergillosis completely. Among patients who developed invasive pulmonary aspergillosis, early diagnosis and treatment are probably the explanation for the favorable outcome.

Adult↗
PubMed2001

Genetically haploidentical stem cell transplantation for acute leukemia.

Genetically haploidentical stem cell transplants have been performed for several decades, mostly for patients with advanced acute leukemia. Such transplants are an option for those patients who do not have a histocompatible sibling donor. The historical data have been disappointing due to graft-versus-host disease, engraftment failure and delayed immune reconstitution. Recent modifications and new technological developments have led to more encouraging clinical results. Haploidentical transplantation is immediately available to the majority of patients with acute leukemia and is an acceptable alternative to matched unrelated donor transplantation.

Acute Disease↗
PubMed2001

Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1.

Tetramethylrosamine (TMR) is excluded from P-glycoprotein (MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent lines. Application of the TMR resistance assay to cells obtained from chronic myelogenous leukaemia (CML) patients revealed, in all individuals, a significant resistance compared with healthy donors (P < 0.001). Cells from the same patients at later phases exhibited a further increase in TMR resistance. Doxorubicin was excluded from all cell samples obtained from CML patients at presentation. The resistance to TMR and doxorubicin was energy-dependent, and was not modulated by inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1). Transcription of mRNAs suspected as relevant to multidrug resistance was assessed using comparative reverse transcription polymerase chain reaction. All cells from the CML patients transcribed high levels of MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1, MRP1, MRP2, MRP6, lung resistance-related protein and anthracycline resistance-associated protein were equally transcribed in cells from healthy donors and CML patients. These results indicated that neither MDR1 nor MRP1 mediate the resistance in these cells. Our results shed light on a resistance mechanism operative in CML patients, which, together with the resistance to apoptosis, is responsible for the lack of response of CML patients to induction-type protocols used to treat acute myeloid leukaemia patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Biology and therapy of secondary leukaemias.

Secondary leukaemias are common, accounting for more than 40% of all patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). A clinical history of exposure to haematotoxins or radiation is helpful; however, many older patients are diagnosed with leukaemia with no antecedent history of exposure. These patients' disease show a remarkably similar phenotype to classic therapy-related leukaemia. The specific cytogenetic abnormalities common to MDS, alkylating-agent-related AML and poor-prognosis AML (3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19,20q-, +21, t(1;7), t(2;11)), probably reflect a common pathogenesis distinct from that of other de novo AMLs, although the pathogenetic pathway has yet to be elucidated. Possibly, tumour suppressor genes are implicated and genomic instability may be a cause of multiple unbalanced chromosomal translocations or deletions. Typically, these patients are either elderly or have a history of exposure to alkylating agents or environmental exposure 5-7 years prior to diagnosis. Another distinct entity affects the mixed lineage leukaemia (MLL) gene located on 11q23. These account for about 3% of patients with therapy-related leukaemia and have a short latency period from exposure, usually to an inhibitor of topoisomerase II. Other therapy-related patients with t(8:21), inv16 or t(15;17) translocations should be treated as any other de novo AML with similar cytogenetics. In summary, the major prognostic factor is related to the pathogenetic mechanisms of the leukaemia. Cytogenetics and molecular features are a better predictor of outcome than patient history. Patients should receive standard induction therapy. However, the long-term outcome is relatively poor; the best results being obtained among patients undergoing allogeneic transplantation.

Cytogenetics↗
PubMed2001

Association of human DEAD box protein DDX1 with a cleavage stimulation factor involved in 3'-end processing of pre-MRNA.

DEAD box proteins are putative RNA helicases that function in all aspects of RNA metabolism, including translation, ribosome biogenesis, and pre-mRNA splicing. Because many processes involving RNA metabolism are spatially organized within the cell, we examined the subcellular distribution of a human DEAD box protein, DDX1, to identify possible biological functions. Immunofluorescence labeling of DDX1 demonstrated that in addition to widespread punctate nucleoplasmic labeling, DDX1 is found in discrete nuclear foci approximately 0.5 microm in diameter. Costaining with anti-Sm and anti-promyelocytic leukemia (PML) antibodies indicates that DDX1 foci are frequently located next to Cajal (coiled) bodies and less frequently, to PML bodies. Most importantly, costaining with anti-CstF-64 antibody indicates that DDX1 foci colocalize with cleavage bodies. By microscopic fluorescence resonance energy transfer, we show that labeled DDX1 resides within a Förster distance of 10 nm of labeled CstF-64 protein in both the nucleoplasm and within cleavage bodies. Coimmunoprecipitation analysis indicates that a proportion of CstF-64 protein resides in the same complex as DDX1. These studies are the first to identify a DEAD box protein associating with factors involved in 3'-end cleavage and polyadenylation of pre-mRNAs.

Animals↗
PubMed2001

Monitoring of busulfan area under the curve: estimation by a single measurement.

Because the busulfan area under the concentration-time curve (AUC) has been correlated with the outcome of bone marrow transplantation (BMT) and the occurrence of veno-occlusive disease after BMT, a rapid determination of AUC is needed to ensure its suitable dosage. The present work describes a method based on combining aliquots from the 10 blood samples collected for an AUC busulfan determination and performing a single determination of the resulting mixture. In 42 patients undergoing a preparative regimen for bone marrow transplantation this combined sample AUC was compared with the regular determined AUC obtained from 10 consecutive samples drawn at various time intervals after dosing. It is apparent that the AUCs calculated by pharmacokinetic analysis using a noncompartmental model package and those obtained by analyzing the sample mixture are very similar ( r = 0.961). The proposed method allows rapid adjustment of the busulfan dose, reducing the number of uncorrected dosages during therapy.

Adult↗
PubMed2001

Acute myeloid leukemia.

Through the hard work of a large number of investigators, the biology of acute myeloid leukemia (AML) is becoming increasingly well understood, and as a consequence, new therapeutic targets have been identified and new model systems have been developed for testing novel therapies. How these new therapies can be most effectively studied in the clinic and whether they will ultimately improve cure rates are questions of enormous importance. In this article, Dr. Jacob Rowe presents a summary of the current state-of-the-art therapy for adult AML. His contribution emphasizes the fact that AML is not a single disease, but a number of related diseases each distinguished by unique cytogenetic markers which in turn help determine the most appropriate treatment. Dr. Jerald Radich continues on this theme, emphasizing how these cytogenetic abnormalities, as well as other mutations, give rise to abnormal signal transduction and how these abnormal pathways may represent ideal targets for the development of new therapeutics. A third contribution by Dr. Frederick Appelbaum describes how AML might be made the target of immunologic attack. Specifically, strategies using antibody-based or cell-based immunotherapies are described including the use of unmodified antibodies, drug conjugates, radioimmunoconjugates, non-ablative allogeneic transplantation, T cell adoptive immunotherapy and AML vaccines. Finally, Dr. John Dick provides a review of the development of the NOD/SCID mouse model of human AML emphasizing both what it has taught us about the biology of the disease as well as how it can be used to test new therapies. Taken together, these reviews are meant to help us understand more about where we are in the treatment of AML, where we can go and how we might get there.

Acute Disease↗
PubMed2000

Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study.

The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P <.0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P <.0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3. 33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P =.0003), with significant evidence of interaction (P =.017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.

Acute Disease↗
PubMed2000

Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience.

Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.

Adolescent↗
PubMed2000

Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission.

Allogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)-identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA-identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction. (Blood. 2000;96:1254-1258)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Adolescent↗
PubMed2000

Phase II trial of 2-chlorodeoxyadenosine in patients with relapsed/refractory acute myeloid leukemia: a study of the Eastern Cooperative Oncology Group (ECOG), E5995.

2-Chlorodeoxyadenosine (2-CdA) is a purine analog which has anti-leukemic activity in phase II trials in pediatric acute myeloid leukemia (AML) patients. An adult phase I trial suggested possible similar activity although neurotoxicity at higher doses was seen. We conducted a phase II trial of 2-CdA in patients with relapsed or refractory AML. 2-CdA was administered by continuous intravenous infusion at a dose of 17 mg/m(2) per day x5 days. Patients not achieving aplasia by day 21 were eligible for a second course of therapy. Fifteen patients (nine relapsed and six refractory AML) were enrolled including seven men and eight women with a median age of 60 years and median ECOG PS of 1. There were five deaths on study due to infections (two), AML (two), or hepatic failure (one). The 2-CdA was well tolerated without severe nausea, vomiting or stomatitis (all <grade 2). No severe neurologic complications related to 2-CdA were seen. Grade 4 myelosuppression occurred in nearly all patients with prolonged periods of pancytopenia and BM hypoplasia seen in most. There were no complete responses, though bone marrow aplasia was achieved in eight patients. 2-CdA as a single agent, in the doses used in this study, is ineffective therapy for relapsed or refractory AML.

Adult↗
PubMed2000

Successful haploidentical bone marrow transplantation in Fanconi anemia.

A 10-year-old girl with Fanconi anemia and severe aplastic anemia underwent a haploidentical BMT from her mother due to lack of a matched family donor. T cell depletion was done by positive selection of CD34 cells with immunomagnetic beads. Due to graft rejection a second haploidentical BMT from the father was successfully undertaken. No immunosuppression was given after the transplant. Immunological reconstitution took approximately 6 months, with no GVHD or severe infections. Such a transplant, containing a large purified CD34 cell fraction with a minimal number of added T cells, should be considered as the treatment of choice for patients with Fanconi anemia if no HLA matched donor is available.

Antigens, CD34↗
PubMed2000

Treatment of acute myelogenous leukemia in older adults.

The overall strategy for the treatment of older adults is summarized in Table 8. Soon after the birth of effective chemotherapy for acute leukemia, the perspective for all patients was summarized as follows: 'With all humility it may be claimed that there are, at least, grounds for hope and encouragement in this recently acquired ability occasionally to halt for a while the formerly unrelenting malignant process known as acute leukemia'. In reviewing the overall survival data for older adults one may feel that we are at a similar juncture in assessing the outcome for this particular population. It is hoped that some of the potential advances may provide greater hope and improved results over the next decade.

Acute Disease↗
PubMed2000

Immune and hematopoietic reconstitution after transplantation of cord blood progenitor cells: case report and review of the literature.

Transplantation using umbilical cord progenitor cells as the source of the stem cells is increasingly recognized as another form of allogeneic transplantation with curative intent. However, the different patterns of hematopoietic and immunological reconstruction have been described in very few patients. A 20-month-old boy presented with acute leukemia. He received standard AML induction and consolidation therapy, after which he underwent allogeneic transplantation using HLA-matched sibling stem cells obtained from the umbilical cord. The preparative regimen consisted of busulfan and cyclophosphamide. White cell recovery, despite concomitant use of G-CSF, was slow, reminiscent of the engraftment pattern without the use of growth factor. Erythroid recovery was best recorded using fetal cell HbF level. Platelet transfusion independence occurred on day +31. Immunologic reconstitution revealed an early NK cell recovery by 6 weeks and progressive T cell recovery until 3 months, with continued increase in counts thereafter. However, the CD4/CD8 ratio remained low even at 14 months post-transplantation. Recovery of B cells was slower until day +120. Proliferative response was within normal range on day +120. This report describes the unique engraftment pattern following umbilical cord blood transplant and emphasizes the pattern of immunological and hematological reconstitution.

Antigens, CD↗
PubMed2000

Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. Eastern Cooperative Oncology Group.

The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined.

Acute Disease↗
PubMed2000

Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant.

BACKGROUND: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. OBJECTIVE: We documented the incidence of acute cutaneous GVHR associated with roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent roquinimex immunotherapy in the period after the transplant. METHODS: Fifteen patients undergoing bone marrow transplantation and roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. RESULTS: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with roquinimex. Ten of 11 evaluable patients receiving roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. CONCLUSION: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by roquinimex did not correlate with a GVL effect in our study of 15 patients with CML.

Adjuvants, Immunologic↗