These data suggest that PET/CT is a useful tool for both, initial staging and follow-up after therapy in patients with MALT lymphoma. Its sensitivity depends on disease location and stage at initial diagnosis.
Reduced-intensity or nonmyeloablative stem cell transplantation (NST) is designed to induce host-versus-graft tolerance by engraftment of donor stem cells. The rationale behind NST is to induce optimal graft-versus-leukemia (GVL) effects for elimination of all malignant cells by donor alloreactive immunocompetent cells as an alternative to standard high-dose myeloablative chemoradiotherapy. NST based on the use of fludarabine, low-dose busulfan, and anti-T-lymphocyte globulin (ATG) was employed in 24 patients aged 3 to 63 years with chronic myeloid leukemia (CML) in first chronic phase (CP). Graft-versus-host disease (GVHD) prophylaxis consisted of low-dose cyclosporine (CSP), in some cases with low-dose methotrexate. Early discontinuation of CSP was attempted in cases of mixed chimerism in an attempt to amplify GVL effects. All 24 patients showed rapid 3-lineage engraftment, mostly without complete aplasia; 6 patients did not require transfusion of any blood products. NST was associated with minimal procedure-related toxicity. The incidence of acute GVHD (grade I or higher) was 54%; however, this incidence increased following CSP withdrawal. After a follow-up of up to 70 months (median, 42 months), 21 of 24 patients remained alive and disease free. The GVL effects induced by donor immunocompetent lymphocytes eradicated all host hematopoietic cells, as evidenced by molecular testing. The Kaplan-Meier probability of survival and disease-free survival at 5 years is 85% +/- 8% (95% confidence interval, 70%-100%). NST may successfully replace myeloablative stem cell transplantation, providing a safer, well-tolerated therapeutic option for all patients with CML in first CP with a matched donor. However, this conclusion must be tested in a prospective randomized clinical trial.
Summary:Relapse is a serious complication following high-dose therapy and autologous bone marrow transplantation (ABMT) for malignant lymphoma (ML). Allogeneic transplantation (alloSCT) is a therapeutic option. However, it is associated with a high incidence of transplantrelated organ toxicity and mortality. We recently reported fast engraftment and minimal transplantrelated toxicity, using fludarabine-based conditioning with reduced amounts of chemotoxic drugs prior to alloSCT. We now present our experience with 23 heavily treated high risk ML patients who underwent matched alloSCT following the same low intensity conditioning. The patients (20 male, three female) were aged 13-63 years. Nineteen had NHL and four HD (resistant disease 12, partial remission 11). Five were post ABMT. Twenty-two patients had fully matched sibling donors, and one a fully matched unrelated donor. Engraftment was fast. There was no rejection or nonengraftment. Organ toxicity was moderate with no liver or renal toxicity Ͼgrade II. Four patients developed Ͼgrade II graft-versus-host disease (GVHD). Seven patients died -four of grade III-IV GVHD and severe infections, two of bacterial sepsis, one of pulmonary failure. Ten patients are alive after 22.5 (15-37) months. Survival and disease-free survival at 37 months are both 40%. Probability of relapse is 26%. These encouraging results suggest that alloSCT following fludarabinebased low intensity conditioning in high-risk patients merits further evaluation. Bone Marrow Transplantation (2000) 25, 1021-1028. Keywords: allogeneic; peripheral blood stem cell transplantation; malignant lymphoma; fludarabine; low intensity conditioning regimen High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT) has gained widespread acceptance as the treatment for aggressive nonHodgkin's lymphoma (NHL) in chemosensitive relapse,
Allogeneic bone marrow transplantation (BMT) is the only effective treatment for hematologic malignancies resistant to conventional chemotherapy. Until recently, no cure existed for patients who relapsed post-BMT. We present our long-term observations on remission induction, after relapse post-BMT, by allogeneic cell therapy (allo-CT) and the feasibility of remission induction in allo-CT-resistant patients by activation of antileukemia effector cells with recombinant human interleukin-2 (rhIL-2) in vitro and in vivo. The longest observation of successful allo-CT (event-free survival, greater than 8 years) was made in a patient with resistant pre-B lymphoblastic leukemia who received infusions with graded increments of donor (female) peripheral blood lymphocytes (PBL) as soon as bulky hematologic and extramedullary relapse was noticed early post-BMT. The patient is currently without evidence of residual host (male) cells as determined by polymerase chain reaction (PCR). Of 17 patients with acute and chronic leukemia in relapse after BMT, 10 were reinduced into complete remission. Four patients with cytogenetic relapse responded to allo-CT alone, while five of six patients with overt hematologic relapse responded only after additional activation of donor with rhIL-2. Allo-CT can, therefore, successfully reverse chemoradiotherapy-resistant relapse of both acute and chronic leukemia. Moreover, in patients resistant to donor lymphocyte infusion, remission can be accomplished by additionally activating donor PBL in vitro and/or in vivo with rhIL-2. Based on our observations, after BMT, allo-CT should be considered the treatment of choice for patients with hematologic malignancies resistant to conventional anticancer modalities. Allogeneic activated cell therapy (allo ACT) should be considered for patients with tumor cells resistant to allo-CT. Although allo-CT, followed if indicated by allo-ACT, can be effective for patients with overt hematologic relapse, reversal of persistent minimal residual disease or documented molecular/cytogenetic relapse early after BMT may also be considered as a possible indication for allo-CT.
Glucocorticoid-initiated granulocytosis, excessive proliferation of granulocytes, persists after cortisol levels are lowered, suggesting the involvement of additional stress mediator(s). In this study, we report that the stress-induced acetylcholinesterase variant, AChE-R, and its cleavable, cell-penetrating C-terminal peptide, ARP, facilitate granulocytosis. In postdelivery patients, AChE-R-expressing granulocyte counts increased concomitantly with serum cortisol and AChE activity levels, yet persisted after cortisol had declined. Ex vivo, mononuclear cells of adult peripheral blood responded to synthetic ARP26 by overproduction of hemopoietically active proinflammatory cytokines (e.g., IL-6, IL-10, and TNF-α). Physiologically relevant ARP26 levels promoted AChE gene expression and induced the expansion of cultured CD34+ progenitors and granulocyte maturation more effectively than cortisol, suggesting autoregulatory prolongation of ARP effects. In vivo, transgenic mice overexpressing human AChE-R, unlike matched controls, showed enhanced expression of the myelopoietic transcription factor PU.1 and maintained a stable granulocytic state following bacterial LPS exposure. AChE-R accumulation and the consequent inflammatory consequences can thus modulate immune responses to stress stimuli.
To study the role of the stress-induced "readthrough" acetylcholinesterase splice variant, AChE-R, in thrombopoiesis, we used transgenic mice overexpressing human AChE-R (TgR). Increased AChE hydrolytic activity in the peripheral blood of TgR mice was associated with increased thrombopoietin levels and platelet counts. Bone marrow (BM) progenitor cells from TgR mice presented an elevated capacity to produce mixed (GEMM) and megakaryocyte (Mk) colonies, which showed intensified labeling of AChE-R and its interacting proteins RACK1 and PKC. When injected with bacterial lipopolysaccharide (LPS), parent strain FVB/N mice, but not TgR mice, showed reduced platelet counts. Therefore, we primed human CD34 ؉ cells with the synthetic ARP 26 peptide, derived from the cleavable C-terminus of AChE-R prior to transplantation, into sublethally irradiated NOD/SCID mice. Engraftment of human cells (both CD45 ؉ and CD41 ؉ Mk) was significantly increased in mice that received ARP 26 IntroductionThe number of circulating blood cells is tightly regulated by cytokines and chemokines capable of immediate response to various stimuli. 1 Adjustment to changing needs involves rapid mobilization of cells from the bone marrow (BM) and the vascular marginal pool in response to inflammation, stress, or injury. 2 An example is inflammation-inducible hematopoiesis, which was thoroughly studied in murine models using bacterial lipopolysaccharide (LPS), the main cell-wall component of gram-negative bacteria. 3 LPS is an endotoxin that stimulates an acute inflammatory response via the CD14 receptor and the Toll-like receptor-4 (TLR4) found on monocytes and tissue macrophages. 4 LPS-TLR4 interaction initiates a signal transduction cascade that leads to the release of pro-inflammatory cytokines, 3 including tumor necrosis factor (TNF)-␣, interleukin (IL)-1, -6, and -8, and others. These cytokines activate the mobilization of hematopoietic cells from the BM 5 and set in motion the migration of leukocytes from blood vessel walls, increasing their numbers in the circulation. 6 The net result of this process is an immediate and dramatic increase in the number of circulating peripheral blood (PB) cells, needed to mount the immune response, accompanied by a corresponding decrease in BM cell numbers, which in turn induces a compensatory increase in their production. 7 Many factors are involved in abating the inflammatory response and allowing the recovery of hemostasis. Acetylcholine (ACh), one of these factors, acts by attenuating the secretion of proinflammatory cytokines at the posttranscriptional level via activation of nicotinic receptors on tissue macrophages. 8 Circulating acetylcholinesterase (AChE) controls the levels of ACh, suggesting promotion of the inflammatory process under AChE excess. 9 There are 3 C-terminally variant forms of AChE: synaptic (S), erythrocytic (E), and readthrough (R). All are ubiquitously expressed in hematopoietic cell lineages, especially in megakaryocytes (Mks) and erythrocytes. [10][11][12] Importantly, AChE contri...
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