Ribosome-lamella complexes in the peripheral blood of patients with chronic lymphocytic leukemia are associated with serological immune deficiency.

The ribosome-lamella complex (RLC) is a cylindrical structure composed of different numbers of circular lamellae with associated particles, regarded as ribosomes, around a central core. Structures resembling RLC, but lacking the typical mature appearance of RLC, have been called pre-RLC. The authors have found RLCs and pre-RLCs in peripheral lymphocytes of 3 patients with chronic lymphocytic leukemia (CLL). The fact that CLL patients with RLCs were in early Rai clinical stages, had good clinical prognostic factors, and did not require immediate therapy indicates that RLCs occurred in the early course of some cases of CLL. Moreover, the presence of RLC was associated with hypogammaglobulinemia M.

Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse.

Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2) per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

Pre-medication practices and incidence of infusion-related reactions in patients receiving AMPHOTEC: data from the Patient Registry of Amphotericin B Cholesteryl Sulfate Complex for Injection Clinical Tolerability (PRoACT) registry.

BACKGROUND: Clinical studies have suggested that rates of infusion-related reactions (IRRs) may be higher with amphotericin B colloidal dispersion (ABCD) versus other forms of amphotericin B. However, these studies did not permit the use of pre-medications upfront, which are now commonly used. Objectives To describe the use of pre-medications and determine the rate of IRRs in the real-world setting. METHODS: PRoACT, a multicentre, worldwide observational registry, captured real-world data about pre-medication practices and IRRs in patients receiving ABCD. Eligible patients were those beginning treatment with ABCD; treatment was according to the site's standard treatment practice. Incidence of IRRs was collected during the first 10 days of ABCD therapy. Clinical response data were collected 12 weeks after treatment start. RESULTS: One hundred and seventy patients from 21 worldwide sites were included (median age 37 years; 52% male). There were a total of 1230 ABCD infusions (mean dose 2.8 mg/kg/day); 90% of the infusions (1105/1230) had pre-medication. Common pre-medications included corticosteroids, antihistamines, paracetamol (acetaminophen) and metamizole. The overall IRR rate was 12% (147/1230) and was lower in infusions with pre-medication (11%) versus no pre-medication (22%), P < 0.001. Corticosteroids were associated with a decreased incidence of IRRs (P < 0.05), while paracetamol and antihistamines were not. The most common IRRs were chills (7%), fever (7%) and rigors (5%). Clearance of the fungal infection occurred in 52% of the participants. CONCLUSIONS: These data suggest a lower rate of IRRs with ABCD than previously reported. Pre-medication is associated with decreased IRR incidence. Corticosteroids in particular appear to decrease IRRs while paracetamol and antihistamines, though commonly used, do not.

The proto-oncogene expression varies over the course of chronic myeloid leukemia.

UNLABELLED: The chronic phase (CP) of chronic myeloid leukemia (CML) is characterized by the expression of chimeric BCR/ABL gene, extended survival, and profligate growth of maturing granulocyte stemline. The accelerated phase (AP) and blast crisis (BC) of CML are usually manifested by additionally acquired oncogene aberrations, resistance to therapy, advancing anaplasia, progressive organomegaly, and increased blast count. Abnormal expression of some proto-oncogenes may accompany or even precede AP or BC of CML. Our objective was to follow-up oncogene expression over time covering different clinical phases of CML. A total of 85 patients [44 females and 41 males; median age 51 years; range 16-75 years] were studied. At the start of the study, 29 patients were in CP, 25 in an AP, and 31 in BC. Temporal variation in expression (percentage positivity per 1000 analyzed cells) of c-kit, c-myc, H-Ras, cyclin A1, p53, bcl-2 and VEGF oncogenic proteins in CP, AP, and BC of CML was studied by immunohistochemical procedures. This was then correlated with parameters of clinical disease (organomegaly, duration of CP, AP, and BC) and laboratory (Hb, WBC and platelet counts, and the percentage of blasts) data. The level of c-kit expression differed significantly over the course of disease (x(2), p = 0 x 025). Antiapoptotic bcl-2 protein increased significantly with the progression of CML (x(2), p = 0 x 005). The expression of c-myc was most pronounced in the AP (Anova, p = 0 x 033) and then tended to decline. There was no significant difference in the level of expression of H-Ras, cyclin A1 and p53 over the course of disease. The expression of VEGF protein was most pronounced in the AP (Anova, p = 0 x 033) and it was inversely correlated with degree of splenomegaly (Pearson, r = -0 x 400, p = 0 x 011) and overall survival (log rank, p = 0,042). CONCLUSION: The changes in oncogene expression, assessed by immunohistochemical approach over the course of CML may have clinical relevance in deciding on and timing of therapy. Temporal distribution of changes in oncoprotein expression in CML requires further study at the molecular level.

Hodgkin's lymphoma relapse in the uterine cervix 15 years after the initial cure.

Uterine cervix is an uncommon site for the presentation of Hodgkin's lymphoma. We describe a 62-year-old woman who developed an unusual relapse of classical Hodgkin's lymphoma, a nodular sclerosis subtype, in the uterine cervix, with propagation to the vaginal wall. She relapsed 15 years after achieving a complete remission of Hodgkin's lymphoma, initially in clinical stage IVB. This late relapse of the Hodgkin's lymphoma was in the clinical stage IEB and the treatment was initiated according to ABVD regimen. After the second course, lethal outcome ensued due to progression of the renal failure, which ensued in the meantime, probably as an adverse effect of the previous therapy.

Signaling status of IgG B cell receptor (IgG BCR) is indicative for an activated state of circulating B cells in multiple myeloma.

Circulating post-switch B cells have been proposed as proliferative and disseminating progenitors in multiple myeloma. It is unclear whether the class-switched antigen receptor expressed at the surface of these cells plays a role in their expansion. In this work, the signaling status of IgG B cell receptor (BCR) isolated from the lysates of peripheral blood lymphocytes of 32 patients with IgG multiple myeloma, at the time of diagnosis, was investigated by examining whether phosphorylation of BCR Igalpha and Igbeta signal transducer factors (co-receptors) or other signaling molecules was abnormal in these cells when compared with healthy controls. In IgG BCR of normal controls, weak phosphorylation of 56 and 61 kDa Src kinase-related proteins and unphosphorylated co-receptors were found. In myeloma, p56 and p61 kDa proteins, co-receptors, and other IgG BCR-associated proteins from the signal cascade were phosphorylated. Myeloma patients can be classified into subgroups by IgG BCR phosphorylation profiles which characteristically coordinated with the level of IgG paraprotein in serum and the stage of disease. There was a correlative trend between the extent of phosphorylation reduction and advanced stage of disease. Reduced phosphorylation was more pronounced with advanced stages of multiple myeloma.

[Pathohistological characteristics of myelodysplastic syndromes: diagnostic and prognostic significance].

INTRODUCTION: Pathohistological (PH) analysis is recommended as basic diagnostic procedure during the investigation of myelodysplastic syndromes (MDS). AIM: The aim of this paper was to investigate diagnostic and prognostic significance of bone marrow PH features in patients with MDS, and its relation to cytological characteristics of bone marrow aspirate. METHODS: Cellularity, disorder of marrow histotopography, quantity of hematopoiesis lineages, cellular atypia, the amount of myeloblasts, and stromal changes were particularly analyzed in trephines of 236 patients with primary MDS. RESULTS: In most cases (78.4%) hypercellular bone marrow was observed, although in 10.2% patients hypocellular subtype of MDS was diagnosed. Erythropoiesis dislocation was present in 64.7% patients, dislocation of MK-poiesis in 50.9% patients, while 61.3% had dislocation of granulopoesis (so-called ALIP phenomenon). In most cases three lineage hyperplasia was present, while relative hypoplasia of E- and MK-lineage was found in 1/4 cases, each, particularly in advanced MDS. Morphological features of dyseritropoiesis and dysmegakaryocytopoiesis were present in 42.5% and 75.7% cases, respectively. Different stages of reticulin and collagen fibrosis were observed in 55.5% patients, while 7.6% had hyperfibrotic subtype of MDS. Comparative analysis of cytological and histological features of MDS bone marrow showed positive correlation between two methods only in respect of estimation of eritropoiesis quantity, presence of dismegakaryocytopoiesis and "reactive" cells. The univariate analysis showed that MK- and G-lineage dislocation, quantity of E- and G-lineage, and presence of dysmegakaryocytopoiesis, were prognostic indicators for short survival and evolution of the disease in MDS patients. However, multivariate analysis showed that only G-lineage dislocation was independent prognostic variable for survival in MDS cases. CONCLUSION: PH analysis is irreplaceable diagnostic procedure during MDS investigation, since it provides reliable information of cellularity, architectural disorganization, number of megakaryocytes and alterations of marrow stroma. In addition, PH analysis provides numerous important prognostic information.

Hypocellular myelodysplastic syndromes: clinical and biological significance.

The article is concerned with incidence, clinical features, response to therapy, and prognosis of patients with hypocellular myelodysplastic syndromes. Bone marrow (BM) cellularity <30% (or <20% in patients >70 yr) was found in 24 of 236 (10.2%) trephine biopsies. Median age was 61 yr, with significant male predominance (M/F=3.0) At diagnosis, median hemoglobin was 83 g/L, median platelet and neutrofil counts were 31x109/L and 1.2x109/L, respectively. According to FAB classification, 17 patients had RA, 6 had RAEB, and only 1 had RAEB-t. Beside marrow hypoplasia, the most prominent PH finding was megakaryocyte hypoplasia and dysplasia, found in two-thirds of cases, each. Comparison between hypocellular and normo/hypercellular MDS cases regarding clinicopathological features showed younger age, more severe cytopenia, less blood and BM blast infiltration, MK hypoproliferation, and more pronounced stromal reactions in former cases. Karyotypic abnormalities were present in 12.5% hypocellular cases, in contrast to 44.6% normo/hypercellular cases (p=0.0025). Eleven patients were treated with supportive therapy alone, six with danazol or androgens, six with immunosuppressive therapy, and one with LDARAC. However, complete or partial response was achieved in only four patients treated with danazol or androgens. None of the patients developed leukemia. Eleven patients died, so marrow insufficiency was the main cause of death. Median survival was 33 mo for hypocellular MDS, and 19 mo for normo/hypercellular MDS (p=0.09). The results confirm the existence of hypocellular variant of MDS, which seems to have better prognosis than those patients with normo/hypercellular disease.

Long-term survivors in myelodysplastic syndromes: clinical and biological characteristics.

Twenty-eight of 285 patients (9.8%) with primary myelodysplastic syndrome (MDS) survived more than 5 yr (long-term survivors). There were 21 females and 7 males, median age 60 yr (range 18-84 yr). None had circulating blasts, and 14 had refractory anemia (RA), 8 RA with ringed sideroblasts (RARS) and 6 RA with excess of blasts (RAEB). Thirty-seven percent of the 27 patients who were karyotyped had an abnormal clone, but none of them had -7/7q- or complex cytogenetic abnormalities. Only one of the 13 patients tested had abnormal (i.e., "leukemic") in vitro growth of GM progenitors. During 5 yr following the diagnosis, none of the 28 patients progressed to AML. Two patients with an initial diagnosis of RA showed progression to RAEB and CMML. After 5 yr, 23 of the 28 long-term survivors had stable disease (follow-up period ranged from 64 to 216 mo). One patient progressed to AML (113 mo after diagnosis) and another to RAEBT (80 mo after diagnosis). Eight asymptomatic patients were not treated and 12 patients received only supportive therapy. Except for 6 of 8 treated patients who responded to low-dose Ara-C, danazol, androgens, or immunosuppressive treatment, prolonged survival seemed to result mainly from the natural course of the disease. Except for Valensia score (p=0.033), other scoring systems (Bournemouth, Dusseldorf, Lille, and IPSS score) proved of relatively limited value in differentiating between intermediate (2-5 yr) and long-term survivors.

[Chromosome 17 abnormalities in patients with primary myelodysplastic syndrome: incidence and biologic significance]. / Abnormalnosti hromozoma 17 kod bolesnika sa primarnim mijeloidisplasticnih sindromima: incidencija i bioloski znacaj.

Cytogenetic analysis has proven to be a mandatory part of the diagnosis of myelodysplastic syndromes (MDS) as well as a major indicator for predicting clinical course and outcome. Aside from the 5q-syndrome, no specific clinico-cytogenetic entity has been reported. To determine the incidence and clinical significance of acquired abnormalities of chromosome 17 in adult primary MDS, we reviewed the cytogenetic features of 271 patients detected at our institution during a 10-year period. Clonal cytogenetic abnormalities were identified in 109 cases. Among them, abnormalities of chromosome 17 were identified in 13 patients (11.9%). Five patients had "single" defects, while in eight patients abnormalities of chromosome 17 were associated with other chromosomal rearrangements ("complex" defects). After chromosomes 5, 7, 8 and 1, abnormalities of chromosome 17 were the most frequent chromosomal rearrangements in our patients with MDS. Following "single" defects of chromosome 17 were identified: del(17)(p12) in two cases, and i(17)(q10), del(17)(q21;q23) and del(17)(q12;q22) in one case each. Two patients with del(17p), one with RAEB-t and the other one with CMML, had an aggressive course of the disease with accelerated leukemic transformation and short survival. Patient with i(17q) had RARS subtype and died soon after diagnosis, while other two cases with interstitial deletions of the long arm of chromosome 17 had RAEB subtype and stable, no progressive course of the disease. Among "complex" karyotypes with abnormalities of chromosome 17 we identified der(17) in four, monosomy 17 in two, and del(17p) and l(17q) in one case each. Most of these patients transformed to acute leukemia and had very short survival. The results of this study suggest that abnormalities of chromosome 17 are frequent finding in MDS. Loss of genetic material in 17p, both in "single" and "complex" defects, seems to be closely related to poor prognosis of MDS patients.

A novel t(2;17) in transformation of essential thrombocythemia to acute myelocytic leukemia.

A transformation of essential thrombocythemia to acute myelocytic leukemia (AML), myelodysplastic syndrome, or agnogenic myelocytic metaplasia is a relatively rare event. It occurs in 1%-4.5% of all patients with either treated or untreated essential thrombocythemia. Cytogenetic changes in the transformation to AML are common. We report the case of a patient treated for essential thrombocythemia with hydroxyurea for 49 months. He developed AML with a t(2;17), which to our knowledge has not been described in the literature.

[Floating spleen with chronic torsion of the pedicle causing splenomegaly and secondary hypersplenism]. / Ektopicna slezina s hronichom torzijom peteljke koja je dovela do splenomegalije i sekundarnog hipersplenizma.

If the spleen is not fixed within the left subphrenic space, it gradually passes into the lower abdomen, where is much more exposed to trauma. Torsion of the splenic pedicle can also occur, causing the infarct necessitating an immediate surgery. Venous stasis causes splenomegaly and sometimes secondary hypersplenism. The authors present 16.5-year old girl with torsion of the splenic pedicle of floating spleen for 720 degrees: in spite of that, the patient had neither splenic infarct nor splenic vein thrombosis, possibly due to thrombocytopenia, but she had splenomegaly and secondary hypersplenism with pancytopenia causing bleeding, sideropenic anemia and mild jaundice. After treatment with iron, the patient underwent splenectomy which resulted in almost immediate rise of the number of all blood cells, and even thrombocytosis. The authors suggest early surgical treatment of the floating spleen, preferably splenopexy, before development of severe complications when splenectomy had to be performed in the majority of patients. Accessory spleens, if present, should be saved.

[Treatment of 36 cases of thrombotic thrombocytopenic purpura]. / Rezultati lecenja trombozne trombocitopenijske purpure na 36 bolesnika.

Thirty-six patients (pts.) with thrombotic thrombocytopenic purpura (TTP) were treated between May 1990 and May 2003. There were 31 women and 5 men; the average age was 37 years. Twenty-five cases were idiopathic and 11 secondary (3 infection--related, 5 occurred during pregnancy and 3 were drug--associated). The mean lag period between the first symptoms and the diagnosis was 8.5 days (in 14 pts. < or = 5; in 22 > 5). On diagnosis neurological symptoms were present in 31, bleeding in 33, fever in 21 and renal impairment in 27 patients. The mean hemoglobin was 67.5 g/L, the mean platelet count was 10 x 10(9)/L, and the mean reticulocytosis was 17%. The mean serum LDH was 1457 IU. Treatment included plasma exchange (PE) in 24 pts. and only plasma infusions in 12 pts. There were 24 complete responders (20 on PE) and 12 deaths (4 on PE); PE significantly improved survival (p < 0.01). There were 5 treatment-related complications due to the infection and bleeding, 17 exacerbations and 4 relapses. The mean time delay before the onset of symptoms and the treatment initiation lasted for 9 days suggesting the poor disease recognition; the mean time delay from diagnosis to PE institution was 6 days, indicating postponed PE. The mean treatment duration in all patients was 18 days; the mean number of PE cycles needed for the platelet count stabilization was 9. Good prognostic indicators of survival were: the longer prodromal period (> 5 days), the secondary form of TTP and the absence of coma at presentation. The use of PE significantly improved survival. TTP is a severe disorder requiring early recognition and diagnosis in general medical care facilities, which should lead to the timely treatment with PE.