Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies

The presence of idiotype-reactive T-cell subsets and their relation to the tumor load were analyzed in 9 patients with monoclonal gammopathy of undetermined significance (MGUS), in 12 patients with multiple myeloma (MM) clinical stage I, and in 9 patients with MM stage II/III. An enzyme-linked immunospot assay was used to identify interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, or IL-4-secreting T cells after stimulation by F(ab')2 fragments of monoclonal IgG. The response to autologous IgG was significantly higher than that induced by isotypic monoclonal IgG. Comparable results were obtained in a proliferation assay (3H-thymidine incorporation). A total of 8 of 9 patients with MGUS, 7 of 12 patients with MM stage I, and 3 of 9 with MM stage II/III had T cells secreting IFN-gamma and/or IL-2 (T helper [Th1] type-1 cells), whereas cells secreting both Th1 and Th2 or Th0 types of cytokines were more frequent in patients with MM, particularly in those with MM stage II/III. The number and frequency of Th1-type cells were significantly higher in MGUS patients as compared with those of MM stage II/III. The results indicate that idiotype-reactive T cells of the Th1 and Th2 or Th0 subsets were present in MGs and might provide indirect evidence that idiotype-reactive Th1-type cells may have a regulatory impact on the human tumor B cells.     

Antineutrophil cytoplasmic antibodies in T-cell receptor alpha-deficient mice with chronic colitis

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCAs) have been detected in approximately 60% of sera from patients with ulcerative colitis. The aim of this study was to examine the presence of ANCAs and distribution of ANCA-producing B cells in the lymphoid tissue of T-cell receptor alpha-deficient (TCR-alpha-/-) mice that develop chronic colitis resembling human ulcerative colitis. METHODS: Sera from 87 TCR-alpha-/- mice were tested for the presence of ANCAs by enzyme-linked immunosorbent assay against a human neutrophil extract and selected antigens and by immunofluorescence study using human neutrophils. Enzyme-linked immunospot assay was used for detecting ANCA-producing cells from spleen, mesenteric lymph node (MLN), or colon. RESULTS: Approximately 70% of sera from TCR-alpha-/- mice showed reactivity against human neutrophil extracts by enzyme-linked immunosorbent assay. Sixty percent of ANCA-positive sera showed a perinuclear reaction pattern. By enzyme-linked immunospot, ANCA-producing cells were detected in MLN and colon and less often in the spleen of TCR-alpha-/- mice with chronic colitis. The predominant immunoglobulin isotype of these autoantibodies was immunoglobulin A in the colon but not in the MLN and spleen. CONCLUSIONS: TCR-alpha-/- mice produce ANCAs. The ANCA (immunoglobulin A isotype)-producing B cells exist primarily in the diseased colonic mucosa of TCR-alpha-/- mice. (Gastroenterology 1997 Dec;113(6):1828-35)     

The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight- year study of 155 patients

Although high-dose chemotherapy and autologous bone marrow transplantation (ABMT) are increasingly being used for the treatment of relapsed and resistant Hodgkin's disease, there have been few large, single-center studies reported with adequate follow-up to allow full evaluation of this therapeutic modality. We present 155 poor-risk Hodgkin's disease patients who received high-dose BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) chemotherapy and ABMT who have been studied over a period of 8 years. All patients had either not attained a remission on mechlorethamine, vincristine, procarbazine, prednisone-type therapy and had poor prognostic features at presentation, not attained a complete remission or relapsed within 1 year of an initial alternating regimen, or not attained remission with two or more lines of treatment. At the time of ABMT the relapse status of the patients was as follows: 46 patients were primarily refractory to induction therapy, 7 were good partial responders, 52 were in first relapse, 37 in second relapse, and 13 in third relapse. Seventy-eight patients had chemoresistant disease, 33 had chemosensitive disease at the time of ABMT, and 44 were untested for chemosensitivity at latest relapse. The procedure related mortality in the first 90 days post-ABMT of 10% overall. At 3 months 43 patients (28%) were assessed as complete responders, 72 patients had a partial response (46%), and 24 patients (16%) had no response or progression of disease. However, by 6 months, 53 (24%) patients were assessed as complete responders and 51 (33%) patients had nonprogressive disease. Forty-five patients had received radiotherapy post-ABMT to residual masses (41 patients) or to previous sites of bulk disease (4 patients). The actuarial overall and progression-free survival at 5 years was 55% and 50%, respectively. On multivariate analysis patients with bulk (masses > 10 cm), heavily pretreated patients (those receiving three or more lines of treatment) and females had a significantly poorer prognosis. Relapse status was also significant for progression-free survival in that patients in second (60%) and third relapse (70%) had a better prognosis than those in first relapse (44%) or with primary refractory disease (33%). Response to prior chemotherapy did not predict for progression-free survival. These results enable comparisons to be made between high-dose chemotherapy with ABMT and conventional dose salvage therapy. Furthermore, although the results as a whole are highly encouraging, certain groups carry an unfavorable prognosis.     

Differential requirements for platelet aggregation and inhibition of adenylate cyclase by epinephrine. Studies of a familial platelet alpha 2-adrenergic receptor defect

We describe a family whose members have impaired platelet aggregation and secretion responses to epinephrine with normal responses to adenosine diphosphate and collagen. Platelet alpha 2-adrenergic receptors (measured using 3H methyl-yohimbine) were diminished in the propositus (78 sites per platelet), his two sisters (70 and 27 sites per platelet), and parents (37 and 63 sites per platelet), but not in two maternal aunts (12 normal subjects, 214 +/- 18 sites per platelet; mean +/- SE). However, the inhibition of cyclic adenosine monophosphate (cAMP) levels by epinephrine in platelets exposed to 400 nmol/L PGI2 was similar in the patients and five normal subjects (epinephrine concentration for 50% inhibition, 0.04 +/- 0.01 mumol/L v 0.03 +/- 0.01 mumol/L; P greater than .05). In normal platelets, the concentration of yohimbine (0.18 mumol/L) required for half maximal inhibition of aggregation induced by 2 mumol/L epinephrine was lower than that for inhibition of its effect on adenylate cyclase (1.6 mumol/L). In quin2 loaded platelets, thrombin (0.1 U/mL) stimulated rise in cytoplasmic Ca2+ concentration, [Ca2+]i, was normal in the two patients studied. The PGI2 analog ZK 36,374 completely inhibited thrombin-induced rise in [Ca2+]i; the reversal of this inhibition by epinephrine was normal in the two patients. Thus, despite the impaired aggregation response to epinephrine, platelets from these patients have normal ability to inhibit PGI2-stimulated cAMP levels. These patients with an inherited receptor defect provide evidence that fewer platelet alpha 2-adrenergic receptors are required for epinephrine-induced inhibition of adenylate cyclase than for aggregation.     

The contribution of neurocognitive situation,physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors

Background/aim There are no extensive studies on the QL in children who completed acute lymphoblastic leukemia (ALL) treatment and currently living without any disease in Turkey. Our study aimed to analyze both the QL and the effects of physical, neurocognitive capacities on QL in childhood ALL survivors aged 7–12 years at the time of recruitment.Materials and methodsPedsQL cancer module 3.0 child and proxy report, for ages 5–7 and 8–12 years, WeeFIM scale, BOTMP Short Form, RPM, reading, writing, and mathematics assessment tools, sociodemographic information form were carried out to the children and their family.Results There was no effect of the months since the completion of therapy on pain, anxiety, cognitive problems, perceived physical appearance, and the total QL scores of children and proxy reports (p > 0.05).Children’s physical capacities were significantly worse than healthy controls and have not reached the level of healthy children even after a long time since completion of ALL therapy. There was a significant association between physical capacity and daily independent living status (p < 0.001). Reading, writing, and mathematical skills were significantly associated with the mean time off-treatment (p < 0.001), and the total score of RPM and PedsQL of those with mathematical difficulties were significantly lower than those without any difficulty (p < 0.05).ConclusionThe months after the treatment (off-treatment time) have not affected total and subunit QL scores. As motor skills difficulties will lead to low academic achievement, early recognition direct the parents for immediate intervention. lead to low academic achievement, early recognition could direct the parents for immediate intervention. Planning psychosocial support programs for physical activity and age-appropriate development of patients from the initiation of treatment will increase the QL in childhood ALL with a survival rate of 80% or more.     

The inhibition of Src kinase suppresses the production of matrix metalloproteinases in from synovial fibroblasts and inhibits MAPK and STATs pathways

Background/aimThe purpose of this study was to investigate the antiarthritic potentials of the inhibition of Src kinase in vivo and in vitro settings. Materials and methodsArthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund’s adjuvant (collagen induced arthritis [CIA] model) in Wistar albino rats. One day after the onset of arthritis, dasatinib, a potent Src kinase inhibitor, (5 mg/kg/day) was given via oral gavage. Tissue Src, Fyn, MAPK and STAT mRNA expressions were determined by real-time polymerase chain reaction. On the other hand, fibroblast like synoviocytes (FLSs) were harvested patients with rheumatoid arthritis (RA) undergoing surgical knee joint replacement. FLSs were stimulated with cytokines and dasatinib was added in different concentrations. MMP –1, –3, and –13 levels in FLSs culture were determined by ELISA.ResultsThe tissue mRNA expressions of Src, Fyn, MAPK and STATs were increased in the arthritis CIA group compared to the control group. Their mRNA expressions in the CIA + dasatinib group were decreased and similar in the control group. In in vitro setting, MMP –1, –3, and –13 expressions from FLSs induced by IL-1β and TNF-α were increased, while dasatinib suppressed their productions from FLSs.ConclusionThe present study shows that the inhibition of Src kinase has antiarthritic potentials in both in vivo and in vitro settings. Src kinase inhibition may be candidate to further research in human RA.