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Biomedical subjects

Y Koc

Publications and source records attributed to Y Koc.

14 recordsLinked to original sources
PubMed2004

Miniaturised nucleic acid analysis.

The application of micro total analysis systems has grown exponentially over the past few years, particularly diversifying in disciplines related to bioassays. The primary focus of this review is to detail recent new approaches to sample preparation, nucleic acid amplification and detection within microfluidic devices or at the microscale level. We also introduce some applications that have as yet to be explored in a miniaturised environment, but should benefit from improvements in analytical efficiency and functionality when transferred to planar-chip formats. The studies described in this review were published in commonly available journals as well as in the proceedings of three major conferences relevant to microfluidics (Micro Total Analysis Systems, Transducers and The Nanotechnology Conference and Trade Show). Although an emphasis has been placed on papers published since 2002, pertinent articles preceding this publication year have also been included.

DNA↗
PubMed2000

Treatment of primary resistant or relapsed multiple myeloma with high-dose chemoradiotherapy, hematopoietic stem cell rescue, and granulocyte-macrophage colony-stimulating factor.

In this prospective, multicenter, phase 2 study, multiple myeloma (MM) patients with primary resistant disease or recurrent chemosensitive disease, in chemoresistant relapse, or in second or subsequent remission were treated with high-dose chemoradiotherapy followed by autologous peripheral blood stem cell (PBSC) rescue. PBSCs were collected using granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg per day subcutaneously for 3 days. Patients underwent high-dose chemoradiotherapy consisting of melphalan (140 mg/m2 x 1 day), cyclophosphamide (60 mg/kg per day x 2 days), methylprednisolone (2 g/d x 7 days), and total body radiation (150 cGy bid x 3 days) followed by peripheral blood stem cell reinfusion (> or = 1.2 x 10(9) mononucleated cells per kg) and GM-CSF support (5 microg/kg per day) and were evaluated for response, survival, and toxicity. Thirty-six patients, median age 53.4 years, completed the study. The mean pretransplantation cumulative melphalan dose was 464 +/- 72 mg. Excluding the 3 patients (8.3%) who failed to engraft, the median times to engraftment and platelet recovery were 10 days (range, 8-39 days) and 17 days (range, 7-67 days), respectively. Four patients (11.1%) died of complications related to the regimen (main causes of death, sepsis and acute respiratory distress syndrome) within the first 100 days. Twenty-two patients (61.1%) achieved complete response (CR), 8 (22.2%) partial response, and 2 (5.5%) no response. Two patients developed myelodysplastic syndrome after achieving CR. For all 36 patients, the probability of overall survival at 5 years was 27.3%. Median survival was 31 months (range, 0.3-81 months) in all patients and 42 months (range, 3.4-81 months) in those with CR. The probabilities of overall and disease-free survival at 5 years for the 22 patients who achieved CR were 43.6% and 15.7%, respectively. This high-dose chemotherapy regimen coupled with PBSC rescue is associated with a high CR rate and is capable of inducing long-term survival in a subset of heavily pretreated patients with primary resistant or recurrent MM.

Adolescent↗
PubMed2000

Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome.

Reactivation of varicella zoster virus (VZV) is a common event in patients undergoing allogeneic bone marrow transplantation (BMT) and may lead to life-threatening complications. We retrospectively analyzed the incidence, clinical outcome, and risk factors for VZV infections occurring within the first 5 years of transplantation in 100 consecutive adults undergoing allogeneic BMT between 1992 and 1997. Forty-one patients (41%) developed VZV reactivation a median of 227 days (range 45-346 days) post-transplantation. Twelve percent of VZV reactivation occurred in the first 100 days and 88% within the first 24 months. Among those who survived for 2 or more years after transplantation (n = 47), 59% developed VZV infection. Forty percent of patients with VZV reactivation required admission with a mean hospital stay of 7.2 days. Two patients developed encephalitis, and 1 died despite antiviral therapy. The most frequent complications were post-herpetic neuralgia and peripheral neuropathy (68%). Thoracic dermatomal zoster represented 41% of the infections; disseminated cutaneous involvement was observed in 17% of patients. No clinical or epidemiologic risk factors were associated with recurrence. Administration of ganciclovir for prevention of cytomegalovirus infection delayed the onset of VZV infection beyond 4 months (P = .06). In a further subset analysis, patients with a limited chronic graft-versus-host disease (GVHD) had a lower estimated incidence of VZV reactivation compared with those with extensive chronic GVHD (P = .11). We conclude that complications from reactivation of VZV infection are common and associated with considerable morbidity and mortality in patients undergoing allogeneic BMT.

2-Aminopurine↗
PubMed1999

Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation.

BACKGROUND: Extramedullary tumors of lymphoid and myeloid blasts outside the well-defined sanctuaries following allogeneic bone marrow transplantation (allo-BMT) are rare. Little is known about the biology, treatment, and outcome of these tumors in this setting. METHODS: In this retrospective analysis, 134 consecutive patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who underwent allo-BMT at a single institution between 1990 and 1998 were reviewed. Five cases of isolated extramedullary myeloid sarcoma that occurred as patterns of recurrence following allo-BMT between 1990 and 1998 are reported. These patients were treated with radiotherapy, systemic chemotherapy, or a second allo-BMT. Clinical outcome is compared with posttransplantation bone marrow relapses observed during the same period at the same institution. The literature on the clinical characteristics, currently available treatment, and outcome of posttransplantation myeloid sarcoma patients was reviewed. RESULTS: Excluding isolated skin and central nervous system recurrences, the frequency of extramedullary myeloid sarcoma encountered as a relapse pattern following allo-BMT was determined to be 3.7% among patients with acute or chronic leukemia of myeloid origin. The survival of patients who were managed with radiotherapy and systemic chemotherapy was less than 4 months. A patient who underwent a second allo-BMT following local radiotherapy is alive and in complete remission more than 33 months after the diagnosis of myeloid sarcoma. The median survival of 17 patients with posttransplantation bone marrow relapse following allo-BMT was 2.2 months. When posttransplantation medullary recurrences are analyzed, patients with CML had a median survival of 12 months, with a significantly better 5-year survival rate than patients with AML (0 vs. 60%, P = 0.015; median survival, 12 months). CONCLUSIONS: The clinical outcomes of patients with recurrent isolated extramedullary myeloid sarcoma following allo-BMT are poor, as in any leukemic relapse, with the exception of patients with CML in this setting.

Adult↗
PubMed1999

Role of splenic irradiation in patients with chronic myeloid leukemia undergoing allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has become the treatment of choice for patients of appropriate age with chronic myeloid leukemia (CML). In an attempt to enhance tumor cytoreduction, splenic radiation therapy (RT) has been done before the allogeneic transplant, but the role of splenic RT in this setting remains controversial. The purpose of this study is to evaluate the role of splenic RT before allogeneic BMT in patients with CML. Thirty-seven patients with chronic (n=33) or accelerated (n=4) phase CML underwent BMT from April 1990 to January 1998. All patients received splenic RT consisting of 500 cGy in five daily fractions (n=36) or 250 cGy in five daily fractions (n=1) completed within 10 days before BMT. The conditioning regimen included total-body irradiation and cyclophosphamide; etoposide was added to the regimen of patients in the accelerated phase. Continuous-infusion cyclosporine and pulse methotrexate were administered to all patients for prophylaxis of graft-vs.-host disease (GVHD). All patients achieved hematologic and cytogenetic remission. At a median follow-up of 37 months, the freedom from progression (FFP) and overall survival (OS) were 90 and 82%, respectively. None of the patients in accelerated phase have relapsed. Five patients have died of late transplant-related complications while in complete remission. Acute GVHD of grade > or = II was observed in 20% (14% grade II, 6% grade III). Fifty-one percent of patients developed limited chronic GVHD. The median posttransplant creatinine level was 1.2 mg/dL (range 0.6-4.2). Renal dysfunction, manifested as a persistent elevation in serum creatinine level (> 1.2 mg/dL), was observed in 40% of the patients. Only 8.5% had a creatinine level > 2.0 mg/dL, and no patient required dialysis as a result of renal dysfunction. Seven patients (18.9%) developed pulmonary complications, which included idiopathic interstitial pneumonitis (two), biopsy-proven interstitial fibrosis (four), and alveolar hemorrhage (one). The low relapse rate observed in this study may reflect the use of splenic RT as a part of the cytoreductive regimen before BMT. The fractionation schedule of 500 cGy in five daily fractions was well tolerated and did not appear to increase the toxicity of the preparative regimen. These favorable results indicate that splenic RT deserves further investigation and may be of benefit as a part of the conditioning regimen for patients receiving allogeneic BMT for CML.

Adult↗
PubMed1999

Early infection in bone marrow transplantation: quantitative study of clinical factors that affect risk.

Infections remain common life-threatening complications of bone marrow transplantation. To examine clinical factors that affect infection risk, we retrospectively studied patients who received bone marrow transplants (53 autologous and 51 allogeneic). Over a median of 27 hospital days, 44 patients developed documented infections. Both autologous transplantation and hematopoietic growth factor use were associated with less prolonged neutropenia and decreased occurrence of infection (P < or = .05). In a survival regression model, variables independently associated with infection risk were the log10 of the neutrophil count (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.32-0.75), ciprofloxacin prophylaxis (HR, 0.42; 95% CI, 0.19-0.95), empirical intravenous antibiotic use (HR, 0.09; 95% CI, 0.03-0.32), and an interaction between neutrophil count and intravenous antibiotic use (HR, 1.86; 95% CI, 1.06-3.29). In this model, infection risk increases steeply at low neutrophil counts for patients receiving no antibiotic therapy. Ciprofloxacin prophylaxis and particularly intravenous antibiotic therapy provide substantial protection at low neutrophil counts. These results can be used to model management strategies for transplant recipients.

Adult↗
PubMed1998

Vancomycin-resistant enterococcal infections in bone marrow transplant recipients.

Vancomycin-resistant enterococci (VRE) infections have been increasingly reported in immunosuppressed individuals over the past decade. Emergence of this pathogen in the bone marrow transplantation (BMT) setting, in the form of bacteremia or positive stool cultures, is of concern because of lack of effective antimicrobial therapy. We report episodes of vancomycin-resistant E. faecium bacteremia in two patients undergoing BMT including the first case of VRE meningitis observed in this setting. Since the outcome in these patients undergoing matched unrelated donor BMT was fatal, we believe that routine screening for VRE in high risk patients should be considered. Management of VRE carrier state in BMT candidates is unclear at present.

Adult↗
PubMed1998

Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells.

Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.

Antineoplastic Agents↗
PubMed1998

Bolus and continuous infusion mitoxantrone in newly diagnosed adult acute lymphoblastic leukemia: results of two consecutive phase II clinical studies.

Two consecutive phase II clinical studies were designed to evaluate the efficacy and safety of bolus and continuous infusion (CI) mitoxantrone (MTZ) in 39 patients with newly diagnosed acute lymphocytic leukemia (ALL). MTZ was used as part of the classical ALL induction regimen. Twenty patients were treated with bolus MTZ (10 mg/m2 for 3 days) combined with vincristine and prednisone. The same regimen was given to a second set of 19 patients, except that MTZ was administered as a 24-hr CI. Both groups received bimonthly intensifications with vincristine and prednisone for 3 years, along with oral maintenance therapy. Patients in the CI-MTZ study arm received additional MTZ on the first day of intensification cycles. Seventeen patients (85%) in the bolus arm and 15 patients (79%) in the CI arm achieved complete remission (CR). Median disease-free survivals (DFS) in the bolus and CI groups were 11 and 15 months after median follow-ups of 16 (3.5-96) and 13 (2.3-32) months, respectively. At 2.5 years, DFS rates were 29.4% and 34.4% in the bolus and CI groups (p > 0.05). There were no significant differences between two groups in rates of early death, degree of organ toxicity, or duration of neutropenia and thrombocytopenia. Significant cardiac toxicity was not observed in either group. Bolus or CI administration of MTZ was equally effective and was well tolerated. Neither the mode of administration nor increasing the dose intensity of MTZ by incorporating intensification cycles reduced relapse rates. Development of new antileukemia agents and novel treatment approaches are still needed to improve the high relapse rates in adult ALL once a complete response is achieved.

Adolescent↗
PubMed1994

Costimulation of cutaneous T-cell lymphoma cells by interleukin-7 and interleukin-2: potential autocrine or paracrine effectors in the Sézary syndrome.

PURPOSE: To examine interleukin-7 (IL7)- and interleukin-2 (IL2)-induced proliferation of Sézary lymphoma cells and to consider if an autocrine or paracrine growth-stimulatory circuit involving IL7 exists in the Sézary syndrome (SS). MATERIALS AND METHODS: Fresh Sézary lymphoma cells were maintained in short-term culture in the presence of cytokines, and growth was measured by incorporation of (3H)-thymidine (TdR). Expression of IL7 and IL7 and IL2 receptors (IL7-R and IL2-R, respectively) was assessed by polymerase chain amplification of first-strand complementary DNA (RT-PCR), by affinity cross-linking of radioactive iodine-125-IL7, and by dual-color fluorescence-activated cell analysis. IL-7 production was measured by immunoassay. RESULTS: Sézary lymphoma cells from seven patients showed synergistic (five of seven) or additive (two of seven) proliferation when cultured in the presence of IL2 and IL7, as compared with culture with either cytokine alone. Two patients with evidence of synergistic stimulation of [3H]-TdR incorporation showed IL7-R gene expression by RT-PCR and IL7 affinity cross-linking. Incubation of all seven patients' cells with IL7 induced coexpression to varying degrees of IL7-R and IL2-R. Sézary lymphoma cells from at least three of five patients studied expressed IL7 mRNA, and skin from three of five patients studied, as well as normal skin, expressed IL7 mRNA by RT-PCR. CONCLUSION: Sézary lymphoma cells respond by proliferation to IL7 plus IL2, and in some instances produce IL7. Therapeutic maneuvers should be pursued to take advantage of this potential autocrine or paracrine growth-stimulatory mechanism.

Cell Division↗