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Kenneth B Miller

Publications and source records attributed to Kenneth B Miller.

10 recordsLinked to original sources
PubMed2006

A novel mutation in the last exon of ATRX in a patient with alpha-thalassemia myelodysplastic syndrome.

We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene (CGA-->TGA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.

Aged↗
PubMed2005

Intensified induction chemotherapy in adult acute myeloid leukemia followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation: an Eastern Cooperative Oncology Group trial (E4995).

The feasibility of intensified therapy in adults < 61-years-old with de novo acute myeloid leukemia (AML) was evaluated by adding high-dose cytarabine (HDAC) to conventional induction therapy and in post-remission therapy prior to peripheral blood stem cell transplantation (PBSCT). Patients were treated with conventional induction therapy (daunorubicin days 1-3 and cytarabine days 1-7), followed by HDAC (2 gm/M2) every 12 h ( x 6) on days 8-10. Patients in complete remission (CR) with HLA-matched siblings were assigned to allogeneic PBSCT; the others received two courses of HDAC (3 gm/M2 every 12 h on days 1, 3, and 5) given 1 month apart. Peripheral blood stem cells were then harvested and infused after high-dose chemotherapy. Of 62 eligible, evaluable patients, 47 (76%) achieved CR. The mortality rate was 10% (6 patients); no deaths occurred during the two post-remission courses of HDAC. Fifteen patients were assigned to allogeneic PBSCT and 32 to autologous PBSCT. All surviving patients have been followed for more than 4 years. Including all patients scheduled to receive autoPBSCT in an intent-to-treat analysis, after a median 5-year follow-up the current, non-actuarial, four-year event-free and overall survival was 47% and 47%, respectively. Intensified induction therapy was associated with more toxicity than conventional induction therapy, and the CR rate did not improve. Nevertheless, intensive post-remission therapy was well tolerated, no treatment-related mortality occurred with autologous PBSCT, and disease-free survival and overall survival were lengthy.

Adolescent↗
PubMed2005

Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation.

STUDY OBJECTIVES: The primary aim was to determine if respiratory and skeletal muscle strength and submaximal exercise capacity were reduced in subjects prior to sibling- or unrelated-donor hematopoietic stem-cell transplantation (HSCT). DESIGN: Prospective observational study. SETTING: Tufts-New England Medical Center, a tertiary referral center in Boston, MA. PATIENTS: All patients (n = 56) undergoing either sibling- or unrelated-donor HSCT from January 1, 2002, to December 31, 2002. MEASUREMENTS: Demographic data, chemotherapy burden, pulmonary function tests (PFTs), maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength (GS), 6-min walk test (6MWT), and survival as of May 21, 2004. RESULTS: PImax was reduced to < 80% predicted in 42% of subjects and to < 60% predicted in 18% of subjects. PEmax was reduced to < 80% predicted in 89% of subjects and to < 60% of predicted in 80% of subjects. A significant correlation was observed between PImax and PEmax (r = 0.65, p < 0.0001). GS was reduced to < 80% predicted in 39% of subjects and < 60% predicted in 15% of subjects. The 6MWT was reduced to < 80% predicted in 58% of subjects and to < 60% predicted in 9.6% of subjects. Diffusing capacity of the lung for carbon monoxide (Dlco) was the only PFT that was significantly correlated with 6MWT distance (r = 0.44, p = 0.015). The mean calculated load of chemotherapy was 14.8 +/- 16.5 U (+/- SD). The mean time elapsed from date of hematologic diagnosis to date of HSCT was 874 +/- 1,109 days. The median survival of the cohort was 374 days (95% confidence interval, 177 to 665 days). Respiratory or skeletal muscle strength, 6MWT distance, or calculated burden of chemotherapy did not predict survival. CONCLUSIONS: Respiratory and skeletal muscle strength and submaximal exercise capacity are reduced in a significant percentage of patients prior to undergoing HSCT. These observations may help explain musculoskeletal weakness that has been reported in the posttransplant period.

Adult↗
PubMed2005

GM-CSF and low-dose cytosine arabinoside in high-risk, elderly patients with AML or MDS.

Priming of leukemic cells with cytokines may enhance the efficacy of cell-cycle chemotherapy. In this study, we utilized these synergistic effects of granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]), hydroxyurea, and low-dose cytosine arabinoside to treat elderly patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). In a single-institution, retrospective study, we evaluated 94 treatments with concomitant hydroxyurea, cytosine arabinoside, and GM-CSF between the years of 1997 and 2003 in high-risk elderly patients with AML or MDS. A total of 80% of patients received all of the GM-CSF doses; 78% of patients received all of the cytosine arabinoside doses. Adverse events were minimal. No patient developed mucositis or alopecia. The most common adverse event was neutropenic fever, which was noted in 57% of patients. Twenty-one percent of patients remained neutropenic after treatment until death or relapse. Sixty-eight percent of patients reached an absolute neutrophil count of greater than 1000 microL in a median of 33.5 days. Our data show an overall response rate of 52%, with a complete response rate of 39% and a partial response rate of 13%. Overall, our study showed that low-dose cytosine arabinoside given by continuous infusion together with continuous infusion GM-CSF and hydroxyurea was well-tolerated and effective in treating elderly AML and MDS patients who were not eligible for standard induction therapy.

Adult↗
PubMed2004

The scratch test.

Explore the source record for details and available documents.

Artifacts↗
PubMed2003

Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease.

Reduced-intensity allogeneic transplantations for myelodysplastic syndrome (MDS) patients have been limited by significant graft-versus-host disease (GVHD), treatment-related mortality, and disease relapse. We treated 18 MDS patients ineligible for standard allogeneic transplantation with a preparative regimen of photopheresis day -7 and -6, pentostatin 4 mg/m(2) by continuous infusion day -5 and -4, and total body irradiation 600 cGy in 3 fractions day -3 and -2, followed by allogeneic stem cell infusion from 6/6 or 5/6 HLA-matched related donors or 6/6 HLA-matched unrelated donors. GVHD prophylaxis consisted of cyclosporin A and a short course of methotrexate. The median age was 54 years (range, 30-70 years). Diagnoses included refractory anemia (n = 2), refractory anemia with ringed sideroblasts (n = 2), refractory anemia with excess blasts (n = 10), refractory anemia with excess blasts in transformation (n = 3), and chronic myelomonocytic leukemia (n = 1). Sixteen of 18 patients developed full donor chimerism with no day +100 transplant-related mortality. Grade II to IV acute GVHD and extensive chronic GVHD developed in 19% and 18% of patients, respectively. Disease relapse occurred in 2 patients. At a median follow-up of 14 months (range, 1-35 months), the 1-year failure-free and overall survival were 64% and 65%, respectively. Our photopheresis and pentostatin-based reduced-intensity preparative regimen for allogeneic bone marrow transplantation in high-risk MDS patients achieves successful donor engraftment and disease remission with less transplant toxicity and grade II to IV acute GVHD.

Adult↗
PubMed2003

Persistence of host dendritic cells after transplantation is associated with graft-versus-host disease.

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in patients undergoing allogeneic bone marrow transplantation following either a conventional or reduced-intensity preparative regimen. In a murine model, inactivation of host dendritic cells (DCs) was associated with a significant reduction in acute GVHD, suggesting that host DCs may play an important role in the pathogenesis of acute GVHD. The role of host DCs in the development of GVHD following allogeneic stem cell transplantation in humans, however, is unclear. We examined DC chimerism in patients with various hematologic malignancies who underwent a reduced-intensity preparative regimen of extracorporeal photophoresis, pentostatin, and reduced-dose total body irradiation (n = 21) or a conventional preparative regimen of cyclophosphamide and total body irradiation (n = 3). Full donor hematopoietic reconstitution was demonstrated in 19 of 21 patients who underwent a reduced-intensity preparative regimen and in all patients who underwent a conventional preparative regimen. Grade 0 to I acute GVHD and limited or no chronic GVHD were observed in 18 patients who underwent a reduced-intensity regimen and 1 patient who underwent a conventional regimen who achieved full donor DC chimerism at day +100 posttransplantation. In contrast, grade II to IV acute GVHD and extensive chronic GVHD were observed in the 2 patients who underwent a conventional regimen and the 1 patient who underwent a reduced-intensity regimen who had host rather than donor DC chimerism. The persistence of host DCs at day +100 posttransplantation is correlated with the development of severe acute and chronic GVHD (P =.001). Host DCs may represent a therapeutic target for reducing GVHD in allogeneic bone marrow transplants.

Adult↗
PubMed2002

Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) has been shown to be an effective therapy for patients with acute and chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation, but its biologic mechanism is not understood. We reported that clinical response to ECP was associated not only with normalization of skewed CD4/CD8 ratios but also with an increase in CD3(-)/CD56(+) natural killer cells and a decrease in the number of CD80(+) and CD123(+) circulating dendritic cells (DCs). To further elucidate the effects of ECP on activated lymphocyte subpopulations and the interaction between effector lymphocytes and antigen-presenting DCs, we isolated and characterized DC populations from patients with chronic GVHD undergoing ECP therapy. Antigen-presenting activity of DCs was measured as proliferation of antigen-stimulated autologous and allogeneic T cells by mixed-lymphocyte reaction (MLR). In MLR assays the proliferation of T cells was decreased in all 10 patients by a mean of 84% (range, 75%-95%; P < or =.002) after a 2-day cycle of ECP and longitudinally over the 12-month course of therapy. Immunophenotypic analysis of DC populations revealed a preponderance of DC1 monocytic dendritic cells in all patients before the initiation of ECP. Nine of 10 patients demonstrated a shift from DC1 to DC2 and as a concordant shift from a predominantly Th1 (interleukin-2 [IL-2], interferon-gamma) to Th2 (IL-4, IL-10) cytokine profile after ECP, and 8 of 10 had a clinical response to ECP. Our results suggest that ECP alters alloreactivity by affecting allo-targeted effector T cells and antigen-presenting DCs.

Antigen Presentation↗