Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Primary effusion lymphoma with aberrant T-cell phenotype in an iatrogenically immunosuppressed renal transplant male: cytologic diagnosis in peritoneal fluid.

Primary effusion lymphoma (PEL) is an unusual class of non-Hodgkin's lymphoma that develops in body cavities, without associated mass lesions. It has been linked to human herpes virus 8 (HHV-8), an etiological factor of Kaposi's sarcoma. Although PEL is a B-cell lymphoma, the neoplastic cells are usually of the "null" phenotype by immunocytochemistry. The relative infrequency of this entity, the absence of wide casuistic allowing a better characterization, and its unfavorable outcome, strongly support the need of a deeper knowledge. We report the clinico-biological findings of a 49-year-old male who was iatrogenically suppressed patient for 29 years because of renal transplantation. This case was diagnosed cytologically as peritoneal PEL and confirmed histologically on peritoneal biopsies. The immune status for both HHV-8 and Epstein-Barr virus (EBV) was evaluated and showed positive immunostaining only for the former. The combination of the immunocytochemistry results with the existence of a clonal rearrangement in the immunoglobulin heavy chain gene (identified by PCR) was compatible with the diagnosis of PEL. The presence of T-cell markers was consistent with the diagnosis of PEL with an aberrant T-cell phenotype.

Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

OBJECTIVES: To evaluate the use of pioglitazone and rosiglitazone, in terms of both clinical and cost-effectiveness in the treatment of type 2 diabetes. DATA SOURCES: Electronic databases and the reference lists of relevant articles, in addition 14 health services research-related resources were consulted via the Internet. REVIEW METHODS: A systematic review of the literature, involving a range of databases, was performed to identify all papers relating to the glitazones. The methodological quality of the included randomised controlled trials (RCTs) was assessed using the Jadad method. A generic proforma for the critical appraisal of modelling studies in health economics was used in systematically reviewing the economic assessment studies identified. This was supplemented by a detailed review of the disease-specific factors within the studies. Where possible, key outcomes were compared. Readers should note that information from the sponsor's submission was submitted in confidence to the National Institute for Clinical Excellence (NICE). Such information was made available to the NICE Appraisals Committee, but has been removed from this version of the report. RESULTS: Of the 1272 studies identified, nine studies met the inclusion criteria. The clinical evidence available showed that glitazones reduce glycosylated haemoglobin by approximately 1%, and are more effective at higher doses than at lower doses. Glitazone treatment is associated with weight gain. No published data were available on the long-term effects of glitazone use. No prospective RCTs were found comparing pioglitazone to rosiglitazone, but the available evidence indicated that the two treatments had similar effects. There are no published economic studies on either pioglitazone or rosiglitazone. Economic evaluations for both glitazones were provided by the manufacturers. Sensitivity analyses undertaken by the assessment team suggest that the cost per quality-adjusted life-year (QALY) of rosiglitazone is most sensitive to dosage and treatment effect, that is, the effect of rosiglitazone on beta-cell function and insulin sensitivity. In the two scenarios where rosiglitazone is compared with metformin and sulfonylurea combination therapy, the cost-effectiveness of rosiglitazone switches from around 10,000 pounds per QALY to being dominated by the comparator strategy. Since the baseline estimate of cost-effectiveness is not robust to changes in the treatment effect and is reliant on the many assumptions included within the metabolic and long-term economic models, caution should be used in interpreting the baseline result. CONCLUSIONS: The clinical evidence available showed that glitazones can reduce glycosylated haemoglobin; however there were no peer-reviewed data available on the long-term effects of their use or any prospective RCTs found comparing pioglitazone with rosiglitazone. No published economic studies on either pioglitazone or rosiglitazone were found, although sensitivity analyses undertaken by the assessment team suggest that the cost per QALY of rosiglitazone is most sensitive to dosage and treatment effect. It is suggested that research already undertaken in this area should be published, preferably in peer-reviewed journals. Direct head-to-head comparisons of the glitazones in combination with metformin or sulfonylurea would be helpful. The current licence arrangements do not allow for routine use of the glitazones in triple oral combination therapy or in combination with insulin. Evidence is emerging of use of the glitazones within such combinations; therefore, prospective RCTs would be useful. These studies could examine short-term transition strategies and longer term management. The impact of the glitazones in delaying transfer to insulin and the impact on long-term outcomes should also be considered for investigation.

Complete regression of primary gastric plasmacytoma following Helicobacter pylori eradication.

We describe the first case of a primary gastric plasmacytoma stage I completely regressed following Helicobacter pylori (H.pylori) eradication. The patient, a 61-year-old man, had a long history of chronic gastritis and gastric ulcers with recurrent gastrointestinal hemorrhage. Diagnosis of H.pylori infection was based on the positive urease breath test, the elevated titers of serum anti- H.pylori antibodies, and the detection of the bacterium in gastric mucosa biopsy specimens. Diagnosis of gastric plasmacytoma was based on the findings of histopathology, immunocytochemistry and in situ hybridization. Eradication of H.pylori with antibiotics was followed by disappearance of endoscopic and histopathologic features of the gastric tumor 3 months after the completion of the treatment. No relapse has been documented 20 months after the initial diagnosis of plasmacytoma. A possible causal relationship between the tumor and the underlying H.pylori infection is discussed.

Two patients with nonimmune chronic idiopathic neutropenia of adults developing acute myeloid leukemia with aberrant phenotype and complex karyotype but no mutations in granulocyte colony-stimulating factor receptor.

It has been suggested that some cases of nonimmune chronic idiopathic neutropenia of adults (NI-CINA) may be considered preleukemic disorders. This paper describes two patients with NI-CINA who developed acute myeloid leukemia (AML) 34 and 64 months, respectively, following NI-CINA diagnosis. Patient 1 presented erythema nodosum and patient 2 polyarthritis of the large joints 9 and 2 months, respectively, before AML. Patient 1 had AML M4 disease associated with aberrant expression of CD7 and CD19 cell surface markers and one abnormal clone in bone marrow karyotype. Patient 2 had myeloid/natural killer (NK) cell leukemia with expression of CD7 and CD56 molecules and four derivative abnormal clones in the karyotype. Both patients had del(5)(q22q35) in common. No mutations in the transmembrane or the intracytoplasmic domain of the granulocyte colony-stimulating factor (G-CSF) receptor were found. The first patient had disease resistant to chemotherapy from the beginning of the treatment and the second following a brief complete hematological remission. On the basis of these observations, we concluded that a causal link of AML with the underlying NI-CINA cannot be presently justified, but the unusual findings noted in our patients prompt the description of additional cases for a further investigation of the relationships, if any, between these two granulocytic disorders.

Patients with non-immune chronic idiopathic neutropenia syndrome have increased splenic volume on ultrasonography.

Clinically detectable splenomegaly is rarely seen in patients with non-immune chronic idiopathic neutropenia syndrome (NI-CINS). Using ultrasound, we estimated splenic volume in 52 NI-CINS patients and 14 age- and sex-matched normal controls by determining the "corrected splenic index" (CSI) from the product of length, width and thickness of the organ expressed in cm3/m2 body surface area. We found that CSI was significantly higher in the group of patients compared to controls (202.8 +/- 82.0 vs. 133.8 +/- 28.1 cm3/m2, P=0.003), and that individual CSI values was inversely correlated with the number of circulating neutrophils (r=-0.5097, P < 0.0001). About 48.1% of the patients had CSI above 190 cm3/m2 body surface, representing the upper 95% confidence limit of values found in the controls. Patients also had increased serum concentrations of pro-inflammatory cytokines and chemokines mainly produced by activated macrophages (IL-1beta, TNF-alpha, RANTES and IL-8), as well as increased serum levels of soluble cell adhesion molecules derived from activated endothelium (sE-Selectin, sICAM and sVCAM). We hypothesize that the increased splenic volume in NI-CINS patients may be due to the accumulation of activated macrophages inside the spleen, possibly as the result of an unrecognized low-grade chronic inflammatory process. The nature of such an inflammation is unknown. A study was designed to search for viral or bacterial genomic material in patients' bone marrow stromal macrophages in which the unknown causal agent might be located.

Increased frequency and specific reactivity of serum antinuclear antibodies in patients with nonimmune chronic idiopathic neutropenia of adults.

This study describes the frequency of serum organ-specific and organ-nonspecific autoantibodies in 157 patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). Forty-two age- and gender-matched volunteers were used as controls. We found that patients with NI-CINA had increased frequency of antinuclear antibodies (ANA) compared to controls (33.1 vs. 9.5%, p = 0.0025), and that ANA positivity inversely correlated with the number of circulating neutrophils (r = -0.2765, p < 0.0001). Speckled pattern of reactivity was seen in 84.6% of ANA-positive patients, and diffuse pattern in the remaining 15.4%. Patients had also increased levels of circulating immune complexes compared to controls (3.30 +/- 2.41 vs. 1.70 +/- 1.19 microg/ml, p = 0.0042), which inversely correlated with the number of circulating neutrophils (r = -0.2405, p = 0.0154) but not with the titer of ANA positivity. No significant differences were found between the patients and the normal controls in the frequency of positive tests for antibodies to dsDNA, Sm, nRNP, SSA, SSB and Scl-70 antigens, or for parietal cell antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), anti-cardiolipin and anti-thyroid antibodies. Serum levels of rheumatoid factor, C-reactive protein (CRP) and complement factors C3 and C4 ranged within normal limits in the patients studied, but a highly significant correlation was noted between the levels of CRP and ANA positivity (r = 0.3936, p < 0.0001). These findings are suggestive of a chronic inflammation in NI-CINA patients which provides the antigenic stimulus for ANA production, and they further support our previously reported suggestion for the possible involvement of such a low-grade chronic inflammatory process in the pathogenesis of neutropenia in the affected subjects.

Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with severe congenital neutropenia.

OBJECTIVE: To investigate further the cellular defect responsible for impaired granulopoiesis in severe congenital neutropenia (SCN), we have evaluated bone marrow (BM) stem cell reserve and function and BM stromal cell myelopoiesis supporting capacity in two patients with SCN. METHODS: BM primitive stem cells and myeloid progenitor cells were assessed using flow cytometry, limiting dilution assay, clonogenic assays, and long-term BM cultures (LTBMC). BM stroma function was assessed by evaluating the ability of irradiated stromal layers from the patients to induce granulocyte-macrophage colony formation (CFU-GM) by normal CD34+ cells. RESULTS: Compared to the normal controls (n = 37), SCN patients displayed a low percentage of CD34+/CD38+ cells (P < 0.05), low CFU-GM colony formation by highly purified CD34+ cells (P < 0.05), low CFU-GM recovery in LTBMC (P < 0.05), and normal primitive stem cells as indicated by the frequency of CD34+/CD38- cells and the number of long-term culture initiating cells. Patient BM stromal layers exhibited normal myelopoiesis supporting capacity as shown by the CFU-GM content of irradiated LTBMC recharged with normal CD34+ cells. In addition, patient LTBMC supernatants displayed 20-fold normal granulocyte colony stimulating factor and 2-fold normal granulocyte-macrophage colony stimulating factor levels. CONCLUSION: These data show that primitive BM stem cells and stromal cells are not affected in SCN patients, while they support further the concept of a primary defect at the myeloid progenitor cell level. To know the differentiation stage at which the underlying defect causes the malfunction will be relevant for further elucidation of its nature at the molecular level.