Showing papers on "Cytopenia published in 2005"

Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia

Abstract: Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.

Partial splenic embolization in patients with cirrhosis: efficacy, tolerance and long-term outcome in 32 patients.

Abstract: Background Although partial splenic embolization (PSE) has been proposed in patients with cirrhosis in cases when thrombocytopenia or neutropenia may cause clinical manifestations or if there are contra-indications to other therapeutic procedures, there are limited data on long-term outcome. We provide a retrospective review of results and the tolerance of all PSE procedures in patients with cirrhosis in our department. Patients and methods Thirty-two consecutive patients with cirrhosis were included over a 6 year period. Indications for PSE were as follows: (1) severe cytopenia preventing necessary antiviral treatment (n=14), percutaneous destruction of hepatocellular carcinoma (n=8) or major surgery (n=3), severe purpura (n=3); (2) painful splenomegaly (n=4). After superselective catheterization, embolization was performed with up to 50% reduction of splenic blood flow. Results Thrombocyte and leucocyte counts increased markedly (185% and 51% at 1 month; 95% and 30% at 6 months). Thirty-one and 20 patients had platelet count >80,000/mm3 at months 1 and 6 vs only one before PSE. Overall, the aim of PSE was achieved in 27 patients (84%) (planned treatment: 20/25; disappearance of purpura and splenic pain: 7/7). Severe complications occurred in five patients (16%): transient ascites (n=2), splenic and/or portal vein thrombosis (n=2) that resolved after anticoagulation therapy, and splenic abscess (n=2) leading to death. These two patients had splenic necrosis >70%. Conclusion In patients with cirrhosis, PSE may resolve cytopenia and the clinical complications related to hypersplenism or splenomegaly. However, due to a high risk of severe complications, particularly splenic abscess, the indications of PSE should be very limited and the extent of necrosis should be strictly controlled during the PSE procedure.

Shwachman‐Diamond syndrome

Abstract: Shwachman-Diamond syndrome (SDS) is an inherited marrow failure disorder with varying cytopenia, pancreatic dysfunction, and metaphyseal dysostosis. SDS is also characterized by a risk of myelodysplasia and leukemia in up to one third of the patients. Over the last 5 years, major advances have been made in understanding the bone marrow phenotype. The gene associated with the disease, SBDS, has recently been identified. Herein we provide an update on the clinical features, the hematopoietic defects, and the genetics of the disease as they are currently understood. We also review the diagnostic and therapeutic approaches to the hematological complications in the syndrome.

Hematologic complications of HIV infection

Abstract: Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) has altered the natural history of human immunodeficiency virus (HIV) infection by decreasing the frequency of opportunistic infections and altering the expected frequency of hematologic complications and AIDS-related malignancies. Thrombotic thrombocytopenic purpura and thrombosis resulting from protein S deficiency are relatively rare complications of HIV in the United States in patients taking HAART, but are frequent in the developing world where these drugs are not available. Cytopenia, particularly anemia, are more common and result both from bone marrow failure and peripheral destruction. Hodgkin's and non-Hodgkin's lymphoma are still problematic in patients with advanced disease with high viral loads. This review will examine and discuss the diagnosis and management of the hematologic complications of HIV.

Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias : a single center preliminary study

Abstract: UNLABELLED Treatment of auto-immune cytopenia refractory to front line therapy with intravenous immunoglobulins and steroids is a matter of concern. We assessed the efficacy and safety of mycophenolate mofetil in a prospective open preliminary study. STUDY DESIGN Adult patients with steroid refractory auto-immune cytopenias were included. Mycophenolate mofetil (MMF) was added to treatment given at the time of inclusion, and efficacy was evaluated in term of improvement of platelet/haemoglobin levels and in term of reduction of previously given drugs, if any. All auto-immune thrombocytopenic purpura (AITP) patients had serologic assessment for associated auto-antibodies at the time of inclusion. Cytopenias associated with other auto-immune diseases, lymphoproliferative diseases or HIV infection were excluded. RESULTS From November 1999 through November 2003, 13 patients were included (nine AITP, three auto-immune haemolytic anaemia (AIHA), one Evans' syndrome; four males, nine females; age: 35-72 yr). For AITP patients, an overall response of 78% was observed. Retrospective analysis showed no significant difference between patients having a short disease duration (<1 yr) and longer disease duration; between patients who previously received more or less than three treatments; and between patients for whom MMF was started as monotherapy or in association with prednisone, However, all AITP patients presenting associated auto-antibodies responded to MMF, while only 50% of patients without associated antibodies were responders. All patients presenting AIHA and Evans' syndrome were responders. The drug was well tolerated, with no significant side effects reported. The cumulative data suggest a potential place for MMF in the treatment arsenal of refractory cytopenias.

Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with infliximab.

Abstract: Anti-TNFalpha strategies can result in significant clinical benefits in rheumatoid arthritis (RA), but with an increased rate of opportunistic infections. Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised hosts, principally in HIV patients. VL in RA patients treated with TNFalpha antagonists is an extremely rare event, and only one case has been described. Here we report a case of VL, occurring after 9 infusions of infliximab in association with azathioprine, in a patient who developed blood cytopenia, fluctuant fever, and splenomegaly.

Splenectomy and preemptive interferon therapy for hepatitis C patients after living-donor liver transplantation.

Abstract: Recurrent hepatitis C after liver transplantation is a major cause of graft failure. We routinely perform preemptive interferon and ribavirin therapy in patients after living-donor liver transplantation indicated for hepatitis C-related cirrhosis. One of the obstacles for the therapy includes blood cytopenia. To overcome this problem, we recently performed splenectomy concurrently with liver transplantation. Thirty-five patients underwent liver transplantation and received preemptive therapy for hepatitis C. They were divided into two groups: those with splenectomy (group A, n = 21) and those without (group B, n = 14). There was no significant difference in the frequency of morbidity between the groups. Platelet counts were well maintained in group A patients during the therapy, and cytopenia led to the discontinuation of the therapy in one group B patient. The results of the preliminary study warrant a randomized control trial to examine the feasibility of splenectomy and preemptive viral therapy during liver transplantation for hepatitis C.

Pancytopenia induced by low-dose methotrexate. A study of the cases reported to the Finnish Adverse Drug Reaction Register From 1991 to 1999.

Abstract: Objective: To study cases of low‐dose methotrexate‐induced pancytopenia with special reference to clinical outcome and factors predisposing to bone marrow suppression.Methods: Patient files of 14 cases of methotrexate‐induced pancytopenia reported to the National Agency for Medicines in Finland from 1991 to 1999 were reviewed. A review of four additional cases was included.Results: Of the 18 patients (median age 72 years), 12 had rheumatoid arthritis, one psoriatic arthritis, five psoriasis without arthritis, and one pemphigus erythematosus. Major co‐morbidity was recorded in 12 patients, and 16 patients used significant concomitant drugs. Eight patients had a mildly or moderately elevated serum creatinine concentration. In every patient the occurrence of cytopenia was abrupt. Eight patients (44%) died, and the most frequent cause of death was infection.Conclusions: Our data show that methotrexate‐induced pancytopenia is associated with high mortality especially in cases with significant co‐morbidity and ...

Anemia in HIV-infected adults: epidemiology, pathogenesis, and clinical management.

Abstract: Anemia is the most common cytopenia seen in people with HIV. Independent of CD4 count and HIV-viral load, anemia has been shown to correlate with increased mortality. Furthermore, successful treatment of anemia has been shown to reduce this risk of death in a comparison with patients with similar immunologic and virologic parameters who are not treated. Women, blacks, injection drug users, and people with advanced disease suffer disproportionally from anemia and should be screened. The pathogenesis of anemia in HIV is complex and may result from opportunistic infections, nutritional deficiencies, AIDS-associated malignancies, medications, or alteration in hematopoeisis induced by HIV itself. A careful review of the patient's past medical history, medications, symptoms, and basic laboratory studies often leads to a treatable cause(s). For patients without secondary causes of anemia, a combination of highly active antiretroviral therapy (HAART) and supplemental erythropoietin leads to improved outcomes. Given the importance of completing therapy on adequate doses of both interferon and ribavirin, effective management of anemia in HIV/Hepatitis C (HCV)-coinfected patients is particularly important.

How we treat Waldenström's macroglobulinemia.

Abstract: Waldenstrom's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma which produces monoclonal immunoglobulin M (IgM). Over the last decade, new treatment modalites have been developed for the management of this disorder. Our objective is to provide treatment recommendations for WM. A review of published reports was facilitated by a MEDLINE computer search and by a manual search of Index Medicus. Other sources included abstracts and conference proceedings. Most patients with WM who are diagnosed by chance without symptoms should not be treated. Initiation of treatment should not be based on level of serum monoclonal protein per se. The presence of cytopenia, significant adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy or cryoglobulinemia indicates the need for treatment. The main choices for primary treatment of symptomatic patients with WM include alkylating agents, the nucleoside analogs fludarabine or cladribine and the monoclonal antibody rituximab or combinations of these programs. There are no data from prospective randomized studies to recommend the use of one program over another. Nevertheless, the need for rapid disease control may favor the use of nucleoside analogs, whereas the presence of significant cytopenia may favor rituximab. High dose therapy with autologous stem cell transplantation may induce responses even in patients with resistance to all three class of agents. It may be prudent to avoid nucleoside analogs in patients who are candidates for high dose therapy. Despite the lack of randomized trials, a rational approach to the treatment of patients with WM is possible. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for autologous stem cell transplantation, age and co-morbid conditions, should be taken into consideration when choosing the most appropriate primary treatment.

Children with myelodysplastic syndrome (MDS) and increasing mixed chimaerism after allogeneic stem cell transplantation have a poor outcome which can be improved by pre-emptive immunotherapy.

Abstract: We recently reported that virtually all children with acute leukaemia and myelodysplastic syndrome (MDS) who develop the phenotype of increasing mixed chimaerism (MC) after allogeneic stem cell transplantation (allo-SCT) will relapse. We therefore performed a prospective, multi-centre study focused on children with MDS (n = 65; advanced MDS = 44, refractory cytopenia = 21) after allo-SCT in order to determine to what extent relapse can be prevented by pre-emptive immunotherapy on the basis of increasing MC. Analyses of chimaerism in 44 patients with advanced MDS revealed 31 cases with complete chimaerism (CC)/low-level MC/transient MC, 11 cases with increasing MC and two cases with decreasing MC. The same analyses in 21 MDS patients with refractory cytopenia revealed 17 cases with CC/low-level MC, one case with increasing MC and three cases with decreasing MC. Pre-emptive immunotherapy performed on each patient that showed increasing MC improved event-free survival from 0%, as seen in prior studies, to 50%. We therefore conclude that pre-emptive immunotherapy is an effective treatment option to prevent impending relapse in children with MDS after allo-SCT.

Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents.

Abstract: Patients with “low-risk” myelodysplastic syndrome (MDS) are mostly treated with approaches aiming to reduce the negative consequences of ineffective hematopoiesis. Transfusion therapy should be tailored to allow adequate oxygenation and optimal quality of life, and may lead to the need for iron chelation therapy. Growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF]) may induce long-lasting improvement of hemoglobin levels and does not increase the risk for leukemic transformation. Growth factors should be offered to defined subgroups of patients. Immunosuppression with antithymoglobulin or cyclosporine A may be an alternative for younger patients with refractory anemia (RA). The new immunomodulating compound lenalidomide, CC5013, is very active in the 5q– syndrome and is under evaluation for other low-risk MDS subtypes. “High-risk” MDS is associated with poor survival and high risk for leukemic transformation. The DNA hypomethylating compounds azacytidine and decitabine may offer improved long-term outcomes in this group of patients, although there has so far been no effect on survival rates. The efficacy of farnesyl transferase inhibitors has been evaluated in a series of phase II trials. The overall response rate was low, but the majority of responses were CRs. Finally, a number of new drugs directed to various biological and genetic targets are entering clinical trials. A thorough diagnostic evaluation is a prerequisite for therapeutic decision-making. Parallel use of the older FrenchAmerican-British (FAB) and the newer World Health Organization (WHO) classifications is helpful in evaluating patients with myelodysplastic syndrome (MDS), but has led to certain problems. 1 The WHO’s distinction between refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS), and the recognition of refractory cytopenia with multi-lineage dysplasia with or without ringed sideroblasts (RCMD+/- RS) are valuable contributions to the prediction of prognosis and response to treatment. 2,3 Similarly, the creation of a new subcategory encompassing patients with isolated deletion of 5q and < 5% blasts (5q– syndrome) reflected a long-recognized clinical entity. However, the WHO classification does not address the problem of classifying patients with severe bone marrow fibrosis, which is a known negative prognostic marker, nor the issue of hypoplastic MDS. Moreover, the border between acute myeloid leukemia (AML) and RA with excess blasts in transition (RAEB-t) remains unclear. Centers that recognize RAEB-t as MDS, as in the FAB system, will be able to assess the response to new treatment modalities specifically in this subgroup. Centers using only the WHO classi

Stem cell transplantation for aplastic anemia and myelodysplastic syndrome.

Abstract: Stem cell transplantation (SCT) from a histocompatible sibling is treatment of choice for severe aplastic anemia. Survival rates have been reported to be as high as 90% for children. Immunosuppressive therapy (IST) is employed in patients who are not candidates for SCT due to donor unavailability. The addition of cyclosporin A to antilymphocyte globulin has improved the response rate to 70-80%, and survival at 5 years among responders is about 90%. In all, 30% of patients treated by IST suffer from relapse, but long-term prognosis does not appear to be affected by this complication. Juvenile myelomonocytic leukemia (JMML) shares both myelodysplastic and myeloproliferative features. Survival (10-year) of patients with JMML without SCT is only 6%. Children with JMML should be transplanted early in the course of their disease. Conditioning regimen composed of three alkylating agents, busulfan, cyclophosphamide and melphalan has been favored by the EWOG-MDS and EBMT-Pediatric WP in the second half of the 1990s. SCT using this conditioning regimen is capable of curing approximately 50% of patients with JMML. More than 70% of patients with refractory cytopenia and more than 50% of children with advanced MDS are cured of by the early performed allogeneic SCT.

Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol.

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of children, affecting predominantly the mononuclear phagocytic system. Previous reports indicate that Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) can also be fatal in many cases, although the prognosis for EBV-HLH is better than for the familial form of hemophagocytic lymphohistiocytosis. We treated four patients with EBV-HLH using immunochemotherapy including steroid, etoposide (VP-16), and cyclosporin, according to the HLH-94 protocol. All patients experienced persistent fever, cytopenia, and hypertriglyceridemia. Serological testing for EBV showed reactivated EBV infections in all patients. EBV DNA detected by PCR and EBV-encoded small RNA measured by in situ hybridization were confirmed in the patients' bone marrow specimens. Hemophagocytosis was shown in bone marrow aspirates and liver biopsy specimen. Complete remission was achieved in all patients after induction and continuation therapy for 4-10 months (median, 7 months) and was maintained for 15-27 months (median, 19 months) without the need for bone marrow transplantation. These results suggest that EBV-HLH can be effectively controlled by immunochemotherapy using the HLH-94 protocol.

Deoxycoformycin (pentostatin) in the treatment of splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes

Abstract: : Background: Splenic marginal zone lymphoma (SMZL) is an infrequent B-cell neoplasm that pursues an indolent course. Signs and symptoms, mostly related to hypersplenism, are successfully managed by splenectomy. However, the therapy of patients who are not fit for a surgical procedure or who relapse after splenectomy, is still an unsettled issue. Patients and methods: We report a phase-II study on 16 patients with SMZL, three therapy naive and 13 pretreated, all showing systemic symptoms or progressive worsening of peripheral cytopenia, who were treated with pentostatin at a dose of 4 mg/m2 every other week for 6–10 wk. In relapsed patients, the median interval between diagnosis and treatment was 26 month (range: 8–49). Results: Overall, 68% of the patients showed a clinical response. Two out three patients, who received pentostatin as first line therapy, attained a complete response (CR). One CR and seven minor or good haematological responses were recorded in relapsed patients. Treatment toxicity, mostly haematological, proved manageable. With a median follow-up of 35 month the median overall survival (OS) is 40 month and the median progression free survival (PFS) is 18 month. Conclusion: Our data show that pentostatin administered every other week has a good degree of activity in the treatment of SMZL and suggest that this schedule could be considered a possible therapeutic option for patients who are not fit for splenectomy or have relapsed.

Partial splenic embolization as pretreatment for antiviral therapy in hepatitis C virus infection.

Abstract: Chronic hepatitis C virus infection is frequently complicated by cirrhosis and hypersplenism, which together with several other factors, such as reduced thrombopoietin synthesis in the liver, cause cytopenia. The antiviral combination therapy with pegylated interferon and ribavirin itself is impaired by haematological toxicity. Partial splenic embolization (PSE) by the injection of microspheres via a catheter comprising approximately 30-70% of the splenic parenchyma is now a safe method, which significantly reduces the cytopenia induced by hypersplenism, especially thrombocytopenia. The effect is long lasting up to 20 years and has been documented in a variety of disorders. PSE is now carefully described in a combination modality as a pretreatment to reduce cytopenia in hepatitis C virus-induced cirrhosis patients with hypersplenism, making antiviral therapy possible per se at higher dosages with a sustained duration.

Splenectomy for splenomegaly exceeding 1000 grams: analysis of 47 patients.

Abstract: Forty-seven patients who underwent splenectomy for splenomegaly > or = 1000 g were studied retrospectively. There were 29 men and 18 women of mean age 56 (range 19-87) years. Haematological malignancy was the most common disorder (42 patients). The main indications for splenectomy were cytopenia (20 patients), diagnosis (14), initial treatment of leukaemia (eight), pain (four) and spontaneous rupture (one). Thirteen patients underwent an associated surgical procedure. One patient died (mortality rate 2 per cent) and 12 (26 per cent) had postoperative complications. The advantages of splenectomy included histopathological diagnosis in 13 of 14 patients with splenomegaly of unknown origin, effective initial treatment in prolymphocytic and hairy cell leukaemia, definitive relief of pain in all affected patients, and long-term improvement of cytopenia in most.

Hepatosplenic αβ T-cell lymphoma with myelodysplastic syndrome

Abstract: We describe a patient with hepatosplenic αβ T-cell lymphoma who showed pancytopenia and myelodysplasia. A 35-year-old man was admitted with fever, pancytopenia, and hepatosplenomegaly but with no lymphadenopathy. We also found trilineage myelodysplasia in the bone marrow on his first admission.The patient had high fever and anemia but no evidence of infection and was tentatively treated with prednisolone. This treatment resulted in a transient improvement of the cytopenia and a reduction of spleen size. However, 10 months after the first manifestation, progression of the splenomegaly and fever became apparent, and a splenectomy was performed. The pathologic findings for the spleen showed diffuse and disseminated infiltration of medium- to large-sized T-lymphocytes in the splenic red pulp. These cells were immunohistochemically positive for CD3, CD5, CD7, CD8, CD16, CD56, T-cell receptor αβ (TCRαβ), T-cell intracellular antigen 1, and granzyme B but were negative for CD4, CD30, CD57, and TCRγδ. These data suggested a diagnosis of hepatosplenic αβ T-cell lymphoma. A Southern blot analysis revealed gene rearrangement of the TCR β-chain gene but not the immunoglobulin heavy chain gene in the spleen cells. An in situ hybridization analysis for the Epstein-Barr virus revealed negative results. The patient received 8 courses of combination chemotherapy and achieved a partial remission; however, the dysplastic features of the marrow cells persisted after the partial remission was obtained. Additional treatment with allogeneic bone marrow transplantation resulted in a transient complete remission; however, the patient relapsed 11 months later. Because he had experienced no lymphadenopathy and showed dysplastic features in the bone marrow, the diagnosis was highly dependent on the pathologic findings for the resected spleen.

Splenectomy for massive splenomegaly.

Abstract: Splenectomy was performed on 47 patients with massive splenomegaly (spleen weight greater than 1.5 kg). With one exception, all patients had a haematological malignancy. The indications for splenectomy were for the diagnosis of unknown cause (n = 5), for the relief of pain (n = 8), as the initial treatment of hairy cell or prolymphocytic leukaemia (n = 8), and for the correction of a haematological cytopenia (n = 26). Splenectomy was completely successful in relieving pain and in establishing a diagnosis, and provided effective palliation in patients with hairy cell and prolymphocytic leukaemia. An immediate correction of a haematological cytopenia was achieved in 24 patients, and the correction was maintained for over 1 year in 11 patients. There were no postoperative deaths and morbidity was acceptably low. We conclude that patients with massive splenomegaly can derive considerable benefit from splenectomy and that massive splenomegaly should not be regarded as a contra-indication to splenectomy.

Multiple littoral cell angioma of the spleen in a case of myelodysplastic syndrome.

Abstract: Littoral cell angioma (LCA) of the spleen is a relatively recently described rare entity, which is associated with haemophagocytosis. In this case report, we will present a case of myelodysplastic syndrome with multiple LCA of the spleen. The patient presented with pancytopenia and multiple haemangiomas were observed in spleen during diagnostic abdominal ultrasound. She required a transfusion of one to two units of packed blood every 4-6 weeks and she eventually underwent a splenectomy in order to decrease the transfusion requirement. Although the patient's pancytopenia improved after surgery, the patient did not achieve a normal haemoglobin level in the two years following the splenectomy. Following further studies, bone marrow aspiration was undertaken and demonstrated minimal dysplasia in erythroid series including nuclear abnormalities, irregular cytoplasmic borders and irregular staining of the cytoplasm. The patient was diagnosed as myelodysplastic syndrome. As LCA of the spleen and myelodysplastic syndrome may both cause cytopenia their co-existence may complicate the clinical presentation leading to an incomplete or inappropriate diagnosis. In cases of haematological disorders with an atypical course, the radiological examination of the spleen should be considered and the possibility of angiomas must be included to the differential diagnosis.

Interleukin 12 and interferon-γ synthetic deficiency is associated with dendritic cell cytopenia after cardiac surgery

Abstract: Traumatic or inflammatory injury associates with deactivation of monocytes and impaired synthesis of proinflammatory cytokines. We conducted a prospective, observational study to test whether cardiac surgery additionally impaired dendritic and natural killer (NK) cell functions responsible for innate immune production of interleukin (IL)-12-dependent interferon (IFN)-gamma in response to bacteria or toll-like receptor agonists. Blood samples were taken just before induction of anesthesia and 24 h postoperatively. LPS- and fixed Staphylococcus aureus-inducible IFNgamma synthesis in whole blood culture after surgery was reduced to 5% of preoperative values (P < 0.001). Production of IL-12 p70, a critical inducer of IFNgamma in the innate immune response, was reduced to 30% of that produced by preoperative samples (P = 0.013). Circulating CD11c, DR myeloid dendritic cells (DC) that are known sources of IL-12 p70 in normal blood, declined to approximately 25% of presurgical numbers (P = 0.004). Experimental depletion of CD11c, but not CD14, cells from normal peripheral blood mononuclear cell (PBMC) similarly disabled Staphylococcus aureus Cowan 1 (SAC)-induced production of IL-12 p70 and IFNgamma. Consistent with SAC-induced IFNgamma expression in CD56 NK and NK-T cells, CD56 depletion ablated IFNgamma production in normal whole blood. However, repletion of IL-12 p70, IL-18, IL-15, and IL-23 in postoperative blood failed to restore presurgical levels of IFNgamma synthesis (P < 0.05). We conclude that DC cytopenia after major surgery is sufficient to explain postoperative IL-12 p70 and IFNgamma synthetic deficiency. In addition, postoperative blood became hyporesponsive to IFNgamma-inducing cytokines as a further contribution to IFNgamma insufficiency. The novel finding of DC cytopenia after major surgery may portend a lack of other immunologic functions provided by this potent accessory cell population.

Cytomegalovirus-associated pulmonary septal capillary injury sine inclusion body change: a distinctive cause of occult or macroscopic pulmonary hemorrhage in the immunocompetent host.

Abstract: The authors describe four patients with symptomatic lung disease morphologically representing a septal capillary injury syndrome temporally associated with serologic and culture evidence of active cytomegalovirus (CMV) infection but without classic cytopathic changes. The authors conducted a thorough review of clinical data, microscopic examination, and in situ hybridization to detect CMV mRNA encoding immediate early protein. The assay detects transcripts that encode early and immediate early proteins. In two cases additional tissue was available for direct immunofluorescent studies. The disease process in each of the patients was morphologically indistinguishable from the pattern of organ injury associated with autoimmune diseases including a small vessel microvascular injury syndrome involving skin and lung and immune complex- mediated glomerulonephritis. Cytopenias were seen in all cases, most commonly thrombocytopenia. All treated patients demonstrated improvement on combined ganciclovir and low-dose steroid therapy. CMV infection may be of pathogenetic importance in some cases of alveolar hemorrhage, especially when accompanied by peripheral blood cytopenia in otherwise healthy patients and if clinical worsening occurs in the setting of a traditional immunosuppressive regimen typically used to treat vasculitis.

Spontaneous remission in adults with primary myelodysplastic syndromes: incidence and characteristics of patients.

Abstract: Reports on spontaneous remissions in patients with primary myelodysplastic syndromes (MDS) occasionally appear in the literature. We report five adult patients with spontaneous remission of MDS, achieved without cytotoxic or any other treatment. These five patients represent 1.6% of 307 MDS patients, diagnosed in our Institute since 1987. According to FAB criteria, three patients had RA, and one patient had RARS and RAEB, each. All patients were women, median age of 63 yr (range 32-68 yr). Patients were without significant complaints and peripheral cytopenia was mild. Bone marrow dyshematopoiesis was also mild, mostly affecting erythroid and megakaryocytic series. At diagnosis, three patients had cytogenetic abnormalities [+8,+12; +15 and del(16)(q22)]. Median time to complete hematological and cytogenetical remission was 51 mo, while median duration of spontaneous remission was 45 mo (range 44-60 mo). As for the follow-up, none of the patients relapsed. In conclusion, although spontaneous remissions (i.e., "regression") of MDS are uncommon, better understanding of their basis may lead to crucial advances in the study of leukemogenesis.

Fisiopatología del síndrome hemofagocítico (linfohistiocitosis hemofagocítica)

Abstract: The hemophagocytic syndrome (hemophagocytic lymphohistiocytosis) is a rare entity which is most commonly seen in children, but can be found at any age. It consists of a combination of cytologically benign proliferation of activated macrophages in bone marrow, spleen, liver or lymph nodes in association with fever, cytopenia, splenomegaly, and hypertriglyceridemia or hypofibrinoge nemia. This can be primary (which is caused by genetic disturbances like PRF1 gene mutations), or secondary (triggered by viral, bacterial, fungal or parasitic infections or in association with malignancies). The diagnosis of the hemophagocytic syndrome is complex and it is practically impossible to differentiate primary from secondary syndrome. In 1991 the Histiocytosis Society developed the diagnostic guidelines for hemophagocytic lymphohistiocytosis. Therapy for this syndrome has only three possibilities: chemotherapy, gamma-globulin therapy, or allogenic bone marrow transplantation. Finally, the prognosis in the primary variant is poor, and is little better for the secondary one, depending on the presence or absence of an underlying cause.

New options in the treatment of myelodysplastic syndrome.

Abstract: Myelodysplastic syndrome (MDS) is a heterogeneous group of progressive chronic hematopoietic disorders, usually presenting as refractory anemia or cytopenia, with an approximately 25% risk of progression toward acute myeloid leukaeima (AML), and no proven curative treatment. Novel biological treatment strategies targeting both the malignant blood cell and its microenvironment can overcome resistance to current therapies, and represent a promising treatment paradigm for improving patient outcome. Many of these agents have multiple biologic activities. The objective of this article is to present a comparative review of classification systems in MDS and to discuss the evolving trends in the treatment of MDS (immunosuppresive therapy, immunomodulatory drugs, arsenic trioxide, proteasome inhibitors, epigenetic therapy).

Prolonged treatment response in aggressive natural killer cell leukemia.

Abstract: We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders.