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1.
Int J Food Microbiol ; 366: 109575, 2022 Apr 02.
Article in English | MEDLINE | ID: mdl-35176610

ABSTRACT

Latilactobacillus sakei comprises a biodiversity of strains, which display different assertiveness upon their application as starter cultures in raw sausage fermentation. While the assertiveness of winning partner strains has been referred to competitive exclusion based on genomic settings enabling occupation of multiple niches of the sausage habitat, single strain assertiveness of L. sakei remained unexplained. In this study we assessed the impact of the expression of a glycosyltransferase enabling the production of a glucan from sucrose to the assertiveness of L. sakei TMW 1.411, which expresses a plasmid-encoded glycosyltransferase (gtf). In a sausage fermentation model wild type L. sakei TMW 1.411 and its plasmid-cured mutant were employed in competition with each other and with other Latilactobacillus sakei strains. To differentiate any effects resulting from general sugar utilization from those of glucan formation, the experiments were carried out with glucose, fructose, and sucrose, respectively. It was shown that the type of sugar affects the individual strains behaviour, and that the wild type was more competitive than the mutant in the presence of any of these sugars. In direct competition between wild type and mutant, a clear competitive advantage could also be demonstrated for the strain possessing the plasmid with the glycosyltransferase. Since this competitive advantage was observed with all sugars, not just sucrose, and Gtf expression has been shown as independent of the employed sugar, it is suggested that possession of the gtf gene-carrying plasmid confers a competitive advantage. It appears that the Gtf contributes to competitive exclusion and the establishment of colonization resistance, to a larger extent by an adhesive functionality of the Gtf on the cellular surface than by the production of glucan. Hence, gtf genes can be used as a possible additional marker for the selection of assertive L. sakei starter strains in sausage fermentation.


Subject(s)
Glycosyltransferases , Latilactobacillus sakei/metabolism , Meat Products , Sugars , Fermentation , Glycosyltransferases/genetics , Meat Products/microbiology , Sugars/metabolism
2.
Leukemia ; 34(4): 966-984, 2020 04.
Article in English | MEDLINE | ID: mdl-32127639

ABSTRACT

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.


Subject(s)
Antineoplastic Agents/therapeutic use , Fusion Proteins, bcr-abl/antagonists & inhibitors , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Aniline Compounds/therapeutic use , Clinical Decision-Making , Consensus Development Conferences as Topic , Dasatinib/therapeutic use , Disease Management , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Gene Expression , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Life Expectancy/trends , Monitoring, Physiologic , Nitriles/therapeutic use , Pyrimidines/therapeutic use , Quality of Life , Quinolines/therapeutic use , Survival Analysis
3.
Hum Reprod ; 33(10): 1915-1923, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30189007

ABSTRACT

STUDY QUESTION: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists? SUMMARY ANSWER: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically. WHAT IS KNOWN ALREADY: In human sperm, the sperm-specific CatSper channel controls the intracellular Ca2+ concentration and, thereby, several crucial stages toward fertilization. CatSper is activated by oviductal ligands and structurally diverse EDCs. The chemicals mimic the action of the physiological ligands, which might interfere with the precisely coordinated sequence of events underlying fertilization. STUDY DESIGN, SIZE, DURATION: For both oviductal ligands and EDCs, we examined in quantitative terms whether stimulation of human sperm in vitro with mixtures results in additive, sub-additive or synergistic actions. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied activation of CatSper in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. The combined action of progesterone and prostaglandins and of the EDCs benzylidene camphor sulfonic acid (BCSA) and α-Zearalenol was evaluated by curve-shift analysis, curvilinear isobolographic analysis and the combination-index method. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis of the action of progesterone/prostaglandin and BCSA/α-Zearalenol mixtures in human sperm by fluorimetry revealed that the oviductal ligands and EDCs both evoke Ca2+ influx via CatSper in a highly synergistic fashion. Patch-clamp recordings of CatSper currents in human sperm corroborated the synergistic ligand-activation of the channel. LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study. Future studies have to assess the physiological relevance in vivo. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that the fertilization process is orchestrated by multiple oviductal CatSper agonists that act in concert to control the behavior of sperm. Moreover, our results substantiate the concerns regarding the negative impact of EDCs on male reproductive health. So far, safety thresholds like the "No Observed Adverse Effect Level (NOAEL)" or "No Observed Effect Concentration (NOEC)" are set for individual EDCs. Our finding that EDCs act synergistically in human sperm challenges the validity of this procedure. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Foundation (SFB 645; CRU326), the Cells-in-Motion (CiM) Cluster of Excellence, Münster, (FF-2016-17), the 'Innovative Medical Research' of the University of Münster Medical School (BR121507), an EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation, and the Innovation Fund Denmark (InnovationsFonden; 14-2013-4). The authors have no competing financial interests.


Subject(s)
Calcium Channels/metabolism , Progesterone/pharmacology , Prostaglandins/pharmacology , Seminal Plasma Proteins/metabolism , Sperm Motility/drug effects , Spermatozoa/metabolism , Calcium Signaling , Dose-Response Relationship, Drug , Endocrine Disruptors/metabolism , Humans , Male
5.
Leukemia ; 26(9): 2061-8, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22627678

ABSTRACT

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Staurosporine/analogs & derivatives , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Adolescent , Adult , Age Factors , Antineoplastic Agents/pharmacokinetics , Drug Administration Schedule , Female , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/mortality , Male , Maximum Tolerated Dose , Middle Aged , Mutation/genetics , Remission Induction , Staurosporine/pharmacokinetics , Staurosporine/therapeutic use , Survival Rate , Tissue Distribution , Treatment Outcome , Young Adult , fms-Like Tyrosine Kinase 3/genetics
6.
Klin Padiatr ; 219(2): 87-90, 2007.
Article in German | MEDLINE | ID: mdl-17405073

ABSTRACT

Asperger syndrome is a disorder within the autistic spectrum, which was first described by Hans Asperger in 1944. It belongs to the group of pervasive developmental disorders and is particularly characterized by qualitative impairments of social interaction and communication as well as distinct special interests and stereotyped patterns of behaviour. We present a patient, showing the typical behavioural symptoms of the Asperger syndrome, which were first diagnosed at the age of sixteen.


Subject(s)
Asperger Syndrome/diagnosis , Adolescent , Affective Symptoms/diagnosis , Affective Symptoms/psychology , Affective Symptoms/therapy , Aggression/psychology , Asperger Syndrome/psychology , Asperger Syndrome/therapy , Communication , Diagnosis, Differential , Humans , Intelligence , Interpersonal Relations , Male , Referral and Consultation , Residential Facilities , Role Playing , Social Behavior Disorders/diagnosis , Social Behavior Disorders/psychology , Social Behavior Disorders/therapy , Social Isolation , Socialization , Stereotyped Behavior
7.
Leukemia ; 17(12): 2358-82, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14562120

ABSTRACT

Novel approaches have been designed to treat leukemia based on our understanding of the genetic and biochemical lesions present in different malignancies. This meeting report summarizes some of the recent advances in leukemia treatment. Based on the discoveries of cellular oncogenes, chromosomal translocations, monoclonal antibodies, multidrug resistance pumps, signal transduction pathways, genomics/proteonomic approaches to clinical diagnosis and mutations in biochemical pathways, clinicians and basic scientists have been able to identify the particular genetic mutations and signal transduction pathways involved as well as design more appropriate treatments for the leukemia patient. This meeting report discusses these exciting new therapies and the results obtained from ongoing clinical trials. Furthermore, rational approaches to treat complications of tumor lysis syndrome by administration of the recombinant urate oxidase protein, also known as rasburicase, which corrects the biochemical defect present in humans, were discussed. Clearly, over the past 25 years, molecular biology and biotechnology has provided the hematologist/oncologist novel bullets in their arsenal that will allow treatment by design in leukemia.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia/drug therapy , Leukemia/physiopathology , Medical Oncology/trends , Humans
8.
Leukemia ; 17(4): 691-9, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12682626

ABSTRACT

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Accelerated Phase/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Benzamides , Biomarkers , Biomarkers, Tumor/analysis , Blast Crisis/therapy , Bone Marrow Examination , Bone Marrow Transplantation , Fusion Proteins, bcr-abl/analysis , Fusion Proteins, bcr-abl/antagonists & inhibitors , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , In Situ Hybridization, Fluorescence , Interferon-alpha/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia, Myeloid, Accelerated Phase/therapy , Life Tables , Neoplasm Proteins/analysis , Neoplasm Proteins/antagonists & inhibitors , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Salvage Therapy , Survival Analysis
9.
Leukemia ; 17(2): 323-7, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12592330

ABSTRACT

Cladribine has been reported to have little activity in fludarabine- refractory chronic lymphocytic leukemia (CLL). We sought to determine whether resistance to therapy with cladribine in fludarabine-refractory CLL patients represented primary drug resistance or the inability to tolerate the myelosuppression associated with this therapy. Patients with fludarabine refractory CLL patients without severe thrombocytopenia (platelets >/=50 x 10(9)/l) or granulocytopenia (neutrophils >1.5 x 10(9)/l) were enrolled. All patients received cladribine (0.14 mg/kg) as a 2-h intravenous infusion daily for 5 days, repeated every 4 weeks. Patients received up to six cycles of therapy. Twenty-eight patients enrolled; 13 had intermediate (Rai stage I or II) and 15 high (Rai stage III and IV) risk stages. No patient had a complete remission, but nine (32%; 95% confidence interval, 15-49%) attained a partial remission when assessed using the modified NCI criteria (1996). The median time to relapse for responders was 12 months, while median progression-free survival for the entire group was 9 months (95% confidence interval, 4-14 months). The median overall survival was 2.2 years (95% confidence interval, 0.8-3.1 years). Response was predicted by pre-treatment Rai status with seven of 13 (54%) intermediate risk vs two of 15 (13%) high-risk patients responding (P = 0.04). Toxicity was myelosuppression and infections (grade 3-5: neutropenia 75%, thrombocytopenia 68%, and infections 43%). Cladribine has modest clinical activity and considerable toxicity in a very selected group of patients with fludarabine-refractory CLL lacking pre-treatment neutropenia and thrombocytopenia.


Subject(s)
Cladribine/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Vidarabine/analogs & derivatives , Vidarabine/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Cladribine/administration & dosage , Cladribine/adverse effects , Confidence Intervals , Disease-Free Survival , Drug Administration Schedule , Drug Resistance, Neoplasm , Humans , Infusions, Intravenous , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Middle Aged , Neoplasm Staging , Patient Selection , Survival Rate , Time Factors
11.
Semin Oncol ; 28(5 Suppl 17): 34-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11740805

ABSTRACT

The development of the targeted signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) has prompted new ways of thinking about the treatment of chronic myeloid leukemia, other sensitive solid tumors such as gastrointestinal stromal tumors, and malignancies in general. The stresses associated with the extraordinary pace of testing and approval of imatinib mesylate provide lessons to government regulatory agencies, pharmaceutical companies, university researchers, professional societies, and the media in terms of their approach to cancer care, drug development, and dissemination of information. Such medical breakthroughs can generate an enormous, and occasionally overwhelming, volume of new information to be assimilated; misinformation and exaggeration should be avoided. Furthermore, in today's Internet age of information, a large fraction of a patient's medical knowledge and/or opinions may have been obtained and forged online, with input from other patients, and patients are clearly more informed about their illnesses and their options than in the past. The availability of imatinib mesylate has already profoundly changed the nature and sequence of treatment recommendations for patients with chronic myeloid leukemia, but a great deal still remains to be learned and new clinical trials must be designed to address numerous questions about the optimal use of this powerful new medication.


Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Signal Transduction/drug effects , Benzamides , Clinical Trials as Topic , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , Interferon-alpha/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Orphan Drug Production
12.
Semin Hematol ; 38(4 Suppl 10): 22-6, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11694948

ABSTRACT

High-grade, B-lineage lymphoproliferative disorders can have a leukemic (acute lymphocytic leukemia [ALL] French-American-British [FAB] stage L-3), a lymphomatous (Burkitt's or small noncleaved [SNC]), or often a mixed clinical presentation in adults. Manifestations of these diseases in both adults and children include a propensity for abdominal and CNS involvement and a high incidence of metabolic abnormalities due to rapid cell growth and turnover, which are acutely exacerbated by treatment. Numerous studies show that FAB L-3, Burkitt's lymphoma (BL), and SNC are among the most curable of the multiple leukemia/lymphoma subtypes if treated appropriately. At least 50% of adults with these disorders are cured with the use of short-term intensive chemotherapeutic regimens, with treatment failure a consequence of both drug resistance and an inability of older adults to tolerate the side effects of therapy. Published studies have included very heterogeneous groups of patients, some characterized only by morphology, and others studied with cytogenetics but not necessarily having the classic mutations involving c-myc. Future studies should focus on better characterizing the patient populations to help identify the patients most likely to benefit from these aggressive regimens, as well as those who might require high-dose therapy with stem-cell transplantation.


Subject(s)
Lymphoproliferative Disorders/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Burkitt Lymphoma/blood , Burkitt Lymphoma/complications , Burkitt Lymphoma/drug therapy , Humans , Lymphoproliferative Disorders/blood , Lymphoproliferative Disorders/complications , Metabolic Diseases/blood , Metabolic Diseases/etiology , Treatment Outcome , Tumor Lysis Syndrome/blood , Tumor Lysis Syndrome/etiology
14.
Cancer Chemother Pharmacol ; 48 Suppl 1: S45-52, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11587367

ABSTRACT

Although 30-40% of newly diagnosed younger patients with acute myeloid leukemia (AML) can be cured with current approaches, the overall outcome has not improved in recent years. In addition, the outcome in adults > 60 years of age remains dismal with < 10% of patients achieving remission remaining alive and disease free. Results of randomized clinical trials in AML evaluating high-dose cytosine arabinoside, changes in anthracyclines, the use of hematopoietic growth factors, stem cell transplantation in first remission, and modulation of the multidrug resistance phenotype are reviewed. New directions for clinical trials include the use of nonmyeloablative allogeneic stem cell transplantation as a form of "immunotherapy", refinements in autologous stem cell transplantation, and possibly manipulations of neoangiogenesis in the bone marrow and incorporation of newer agents, such as gemtuzumab zogamicin into treatment regimens. It is likely, however, that future advances will be a consequence of a better understanding of the biology of leukemic stem cells, and issues related to such studies are discussed.


Subject(s)
Leukemia, Myeloid/therapy , Acute Disease , Antibiotics, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/administration & dosage , Combined Modality Therapy , Cytarabine/administration & dosage , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Granulocyte Colony-Stimulating Factor/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid/drug therapy , Middle Aged , Randomized Controlled Trials as Topic
15.
J Clin Oncol ; 19(20): 4014-22, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-11600602

ABSTRACT

PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin's lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL). PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation. RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty-three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia. CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Drug Administration Schedule , Etoposide/administration & dosage , Female , Humans , Ifosfamide/therapeutic use , Infections/chemically induced , Injections, Spinal , Lymphoma, Non-Hodgkin/pathology , Lymphoma, Non-Hodgkin/radiotherapy , Male , Methotrexate/administration & dosage , Neutropenia/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/radiotherapy , Prednisone/administration & dosage , Survival Analysis , Thrombocytopenia/chemically induced , Vincristine/administration & dosage
17.
J Clin Oncol ; 19(16): 3611-21, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11504743

ABSTRACT

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Respiratory Tract Infections/mortality , Skin Diseases, Infectious/mortality , Administration, Oral , Adult , Aged , Aged, 80 and over , Chlorambucil/administration & dosage , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Middle Aged , Ontario , Respiratory Tract Infections/complications , Skin Diseases, Infectious/complications , Treatment Outcome , United States , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives
18.
Blood ; 98(3): 548-53, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11468148

ABSTRACT

The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients. (Blood. 2001;98:548-553)


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/administration & dosage , Leukemia, Myeloid/drug therapy , Actuarial Analysis , Acute Disease , Aged , Cytarabine/standards , Cytarabine/toxicity , Disease-Free Survival , Dose-Response Relationship, Drug , Double-Blind Method , Follow-Up Studies , Humans , Leukemia, Myeloid/complications , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/standards , Mitoxantrone/toxicity , Remission Induction , Survival Rate , Time Factors , Treatment Outcome
19.
Blood ; 97(11): 3574-80, 2001 Jun 01.
Article in English | MEDLINE | ID: mdl-11369653

ABSTRACT

Multiparameter flow cytometry (MFC) has the potential to allow for sensitive and specific monitoring of residual disease (RD) in acute myeloid leukemia (AML). The use of MFC for RD monitoring assumes that AML cells identified by their immunophenotype at diagnosis can be detected during remission and at relapse. AML cells from 136 patients were immunophenotyped by MFC at diagnosis and at first relapse using 9 panels of 3 monoclonal antibodies. Immunophenotype changes occurred in 124 patients (91%); they consisted of gains or losses of discrete leukemia cell populations resolved by MFC (42 patients) and gains or losses of antigens on leukemia cell populations present at both time points (108 patients). Antigen expression defining unusual phenotypes changed frequently: CD13, CD33, and CD34, absent at diagnosis in 3, 33, and 47 cases, respectively, were gained at relapse in 2 (67%), 15 (45%), and 17 (36%); CD56, CD19, and CD14, present at diagnosis in 5, 16, and 20 cases, were lost at relapse in 2 (40%), 6 (38%), and 8 (40%). Leukemia cell gates created in pretreatment samples using each 3-antibody panel allowed identification of relapse AML cells in only 68% to 91% of cases, but use of 8 3-antibody panels, which included antibodies to a total of 16 antigens, allowed identification of relapse AML cells in all cases. Thus, the immunophenotype of AML cells is markedly unstable; nevertheless, despite this instability, MFC has the potential to identify RD in AML if multiple antibody panels are used at all time points. (Blood. 2001;97:3574-3580)


Subject(s)
Immunophenotyping , Leukemia, Myeloid, Acute/immunology , Neoplasm, Residual/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal , Antigens, CD/analysis , Antigens, CD19/analysis , Antigens, CD34/analysis , Antigens, Differentiation, Myelomonocytic/analysis , CD13 Antigens/analysis , CD2 Antigens/analysis , CD56 Antigen/analysis , Female , Flow Cytometry , Humans , Lipopolysaccharide Receptors/analysis , Male , Middle Aged , Recurrence , Sensitivity and Specificity , Sialic Acid Binding Ig-like Lectin 3
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