Minimal residual disease in childhood B-lineage lymphoblastic leukemia. Persistence of leukemic cells during the first 18 months of treatment

BACKGROUND. Whether patients in clinical remission for acute lymphoblastic leukemia (ALL) continue to harbor leukemic cells is not known, because methods of detecting residual malignant cells have not been sufficiently sensitive. This information might be useful for predicting recurrence and determining the duration of therapy. METHODS. Using a sensitive new method--identifying complementarity-determining region III sequences with the polymerase chain reaction--we estimated the number of residual leukemic cells in the bone marrow of eight children with B-lineage lymphoblastic leukemia before and after remission. RESULTS. Induction chemotherapy produced a 3-to-4-log reduction in the number of leukemic cells. In all samples obtained up to 18 months after diagnosis, however, 0.004 to 2.6 percent of bone marrow nucleated cells were residual leukemic cells. Among the four patients studied more than 18 months after diagnosis, three had no detectable leukemic cells in marrow samples. Despite this, one of them, who was no longer receiving therapy, had a central nervous system relapse. In one patient receiving maintenance chemotherapy, there was a 60-fold increase in leukemic cells three months before bone marrow relapse. CONCLUSIONS. The complete disappearance of leukemic cells (or their reduction below our method's threshold of detection, 1 in 100,000 cells) may be necessary to achieve a cure of ALL. The quantification of residual leukemic cells in serial marrow aspirates during therapy may allow the early detection of relapse.     

Immunogenetic studies in families with rheumatoid arthritis and autoimmune thyroid disease.

HLA and Gm typing were carried out in 16 families. Seven families included 10 sib pairs with rheumatoid arthritis (RA) and autoimmune thyroid disease (ATD) respectively, and nine families included 16 sib pairs with RA and circulating thyroid autoantibodies respectively. Eight, 11, and seven sib pairs with either RA or clinical or immunological evidence of ATD shared none, one, and two HLA haplotypes respectively, and two, seven, and two informative sib pairs shared none, one, and two Gm haplotypes respectively. This random haplotype sharing of HLA and Gm haplotypes suggests that non-HLA, non-Gm linked genes are likely to be involved in any genetic predisposition common to RA and ATD.     

Histological and ultrastructural appearance of the hydroxyapatite-bone interface

This article describes the histological and ultrastructural appearance of the interface created in the implantation bed, between bone tissue and implants made of dense sintered hydroxyapatite (HA). Biopsies from dog subjects included: a) loaded permucosal dental implants for tooth substitution, b) subperiosteally placed implants for alveolar bone correction, c) endosseously placed dental root implants to retain ridge form following extraction. The light and electron microscopical results show extensive bone apposition on the osseous sides of the implant surfaces. There is an intimate, direct bone contact without any visible interruption. The bone is of normal lamellar type and continuously connected with the trabecular bone. Bone has grown into the finest surface irregularities of the implant. Collagen fibers of the calcified bone matrix are observed within a distance less than 500 A from the implant surface. The thin (20-100 A) electron dense layer at the bone-implant interface resembled the lamina limitans of organic bone matrix, also seen at the inner walls of the osteocytes lacunes. Deposition of bone gives rise to a biologically stable bone-implant interface, without disturbance of the physiological bone turnover. This is seen as very favorable for desired long term fixation of implant to bone.     

Three-year durability of dual-nucleoside versus triple-nucleoside therapy in a Thai population with HIV infection

We compared the long-term immunologic and virologic efficacy of the dual- and triple-nucleoside therapy for HIV infection. This was a retrospective analysis of 2 randomized clinical trials in antiretroviral-naive patients. In the dual-nucleoside group, 15 started with didanosine (ddI) monotherapy and then added stavudine (d4T) after 24 weeks, 63 started with various doses of d4T and ddI, and 53 started with zidovudine (ZDV) and lamivudine (3TC). In the triple-nucleoside group, 53 started with ZDV, 3TC, and ddI. After 48 weeks, patients who were not failing were randomized to immediate (before treatment failure) versus delayed (at the time of virologic failure) switching from ddI and d4T to ZDV and 3TC or vice versa and from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC). Failure was defined as a plasma HIV-1 RNA level>or=1 log10 above nadir or >or=10,000 copies/mL when nadir was <500 copies/mL. Patients failing therapy before week 48 received the new treatment as in the immediate switching group. Hydroxyurea was added to the last treatment regimen if patients failed after week 96. CD4 count and plasma HIV-1 RNA level (branched DNA assay with a cutoff point of 50 copies/mL) at week 144 were analyzed by intention to treat. Compared with the dual-nucleoside group, the triple-nucleoside group had a higher proportion of patients with <50 copies/mL at 144 weeks (60% vs. 18%; P<0.001), higher median CD4 count (388 cells/microL vs. 346 cells/microL; P=0.018), and longer duration of response, defined as the time from onset of viral suppression (<500 copies/mL) to the time of treatment failure (the first of 2 consecutive HIV-1 RNA measurements >500 copies/mL never followed by 2 consecutive visits showing suppressible viremia to <500 copies/mL) or discontinuation from the study (144 weeks vs. 104 weeks; P=0.002). Multivariate regression analyses showed that significant predictors for treatment success, defined as a plasma viral load <50 copies/mL at week 144, were asymptomatic clinical status at enrollment, a baseline plasma viral load 相似文献   

Pentasomy 8q in therapy-related myelodysplastic syndrome due to cyclophosphamide therapy for fibrosing alveolitis

Trisomy 8/8q is a common cytogenetic event in myelocytic malignancies, ranging from myelodysplastic syndrome (MDS) to acute myelocytic leukemia (AML) to blastic transformation of chronic myelocytic leukemia. Isochromosome 8q results in the same gene dosage effect. Duplication of i(8q), resulting in pentasomy 8q, has been reported only in two cases of AML. A patient with fibrosing alveolitis on prolonged cyclophosphamide treatment developed therapy-related MDS. Karyotyping, FISH, and CGH analysis showed a duplicated i(8q) among other complex abnormalities. The clinical features of 11 cases of myelocytic leukemia with pentasomy and hexasomy 8/8q were summarized. Compared with trisomy and tetrasomy 8, significant features included reduced median survival (90 days), treatment refractoriness (even with transplantation), monocytic differentiation, trilineage dysplasia, and radiation or toxin exposure. Increasing copy numbers of chromosome 8/8q may therefore be a marker of advanced leukemic evolution, exposure to toxins, underlying myelodysplasia, and an overall poor prognosis.     

Significant differences between plasma HIV-1 RNA assays in HIV-1 subtype E infected patients treated with antiretroviral therapy

A total of 72 HIV-1 infected Thai patients treated with didanosine (ddI) or stavudine (d4T) plus ddI at the time of interim analysis were analyzed. Sixty patients (83%) carried subtype E documented by HIV-1 V3 serotyping. HIV-1 RNA levels were measured using three commercial viral load assays. At baseline (n = 57), Quantiplex 2.0 and NucliSens 2.0 showed mean log10 HIV-1 RNA of 0.7 log10 or 5 fold lower than Amplicor 1.5 (mean 4.29 versus 5.0 log10, respectively, p < 0.001). At week 20 of treatment (n = 29), HIV-1 RNA levels were detected in 55.2%, 31%, and 33.5% of subjects tested by Amplicor 1.5, Quantiplex 2.0, and NucliSens 2.0, respectively. In conclusion: plasma HIV-1 RNA analyses showed comparable values with Quantiplex 2.0 and NucliSens 2.0 assays. In contrast, Amplicor 1.5 resulted in approximately 5 folds higher HIV-1 RNA levels and a 25% higher rate of detection of plasma HIV-1 RNA as compared to the other two assays. As the current goal of therapy is to suppress plasma viral load below the detection limit of the assays, the significant differences between the assays may influence antiretroviral efficacy evaluation and management.     

Rheumatoid arthritis

Summary: Therapeutic efficacy of depleting B cells or blocking T‐cell costimulation in rheumatoid arthritis (RA) has confirmed the critical pathogenic role of adaptive immune responses. Yet, RA preferentially affects elderly individuals, in whom adaptive immunity to exogenous antigens begins to fail. Here, we propose that senescence of the immune system is a risk factor for RA, with chronic inflammation resulting from the accumulation of degenerate T cells that have a low threshold for activation and utilize a spectrum of novel receptors to respond to microenvironmental cues. The process of immunosenescence is accelerated in RA and precedes the onset of disease, the acceleration, in part, being conferred by the HLA‐DR4 haplotype. Naive CD4⁺ T cells in RA are contracted in diversity and restricted in clonal burst. Senescence of effector CD4⁺ T cells is associated with the loss of CD28 and the de novo expression of KIR2DS2, NKG2D, and CX₃CR1, all of which function as costimulatory molecules and reduce the threshold for T‐cell activation. The synovial microenvironment promotes chronic persistent immune responses by facilitating ectopic lymphoid neogenesis, such as the formation of aberrant germinal centers. With the propensity to develop complex lymphoid architectures and to provide optimal activation conditions for senescent CD4⁺ T cells, the synovium becomes a natural target for pathogenic immune responses in prematurely aged individuals.