The potential role of recombinant activated FVII in the management of critical hemato-oncological bleeding: a systematic review.

Recombinant activated factor VII (rFVIIa) is an hemostatic agent that was originally developed for the treatment of hemorrhage in patients with hemophilia and inhibitors. However, in the last few years rFVIIa has been employed with success in a broad spectrum of congenital and acquired bleeding conditions. In this systematic review we present the current knowledge on the use of this drug in patients suffering from hemato-oncological disorders, which are quite commonly complicated by severe hemorrhage. On the whole, data in the literature suggest a potential role for rFVIIa in the management of bleeding unresponsive to standard therapy in patients with hematological malignancies, including those undergoing bone marrow transplant. However, the vast majority of the currently available data are derived from uncontrolled studies including single cases or small series of patients. Thus, further trials with larger numbers of patients are needed to establish the most appropriate doses and timing of rFVIIa and to assess its efficacy and safety in this setting.

Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin's disease and correlate with clinical features and prognosis.

PURPOSE: To evaluate the serum levels of the soluble form of the CD30 molecule (sCD30) in patients with Hodgkin's disease (HD) to establish whether there is a correlation with clinical features at presentation and prognosis. PATIENTS AND METHODS: The sCD30 serum levels of 117 patients were measured at diagnosis with a commercial sandwich enzyme-linked immunoadsorbent assay (ELISA) test kit, and in 78 of these patients the sCD30 levels were also recorded during the follow-up period. RESULTS: sCD30 levels at diagnosis were increased (> 20 U/mL) in a high proportion of patients (87.2%; mean +/- SD, 108 +/- 134 v 5.3 +/- 5.7 U/mL in controls, P < .0001) and correlated with stage (stages I + II, 73 +/- 97 U/mL; III + IV, 162 +/- 165 U/mL; P < .0001), with presence of B symptoms (stage A, 69 +/- 82 U/mL; stage B, 162 +/- 171 U/mL; P < .0001), and, to some extent, with tumor burden (bulky presentation, 141 +/- 129 U/mL; nonbulky, 91 +/- 133 U/mL; P = .058). Patients with sCD30 levels greater than 100 U/mL at diagnosis had a significantly higher rate of poor outcome in terms of failure to achieve a complete remission (CR) or disease relapse after CR achievement. In fact, the event-free survival (EFS) duration of patients with sCD30 levels greater than 100 U/mL was significantly worse (P = .0016). Using multivariate analysis, an sCD30 level greater than 100 U/mL retained its significance after adjustment for other prognostic parameters. CONCLUSION: sCD30 in HD at presentation strictly correlates with clinical features. Serum levels greater than 100 U/mL at diagnosis entail a significantly higher risk of treatment failure, a factor that is independent of other prognostic parameters.

Mediastinal large-B-cell lymphoma with sclerosis: a clinical study of 21 patients.

We report the clinical findings of 21 consecutive patients affected by mediastinal large B-cell lymphoma with sclerosis. This type of lymphoma is a recently described histopathologic entity characterized on clinical grounds by distinctive features, which, according to our series, can be summarized as follows: young age (median, 30 years; range, 15 to 42 years), prevalence of females over males (15 v six), rare occurrence of superficial lymph node enlargement (three of 21 patients), and involvement of unusual extranodal sites (kidney six, adrenal cortex two patients). The clinical course appears to be closely related to treatment. In fact, complete remission (CR) was not obtained in the six patients submitted to conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus bleomycin (CHOP-Bleo) regimens until 1985, as opposed to 13 CRs reached in the 15 patients subsequently treated with more aggressive regimens after 1985 (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B], 12 patients; methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone [M-BACOD], two patients; and vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate, and prednisone [F-MACHOP], one patient; plus involved-field radiotherapy, 10 patients). Among the 13 patients who achieved a CR, only one relapse was observed at 10 months. The median overall survival of complete responders after an observation period of 11 to 69 months has not yet been reached, and the event-free survival curve indicates that 90% of patients who achieve CR may be potentially cured.

Relationship between Daunorubicin dosage delivered during induction therapy and outcome in adult acute lymphoblastic leukemia.

The long-term results of a therapeutic regimen for adult acute lymphoblastic leukemia (ALL) have been analysed with the main purpose to evaluate the impact of Daunorubicin (DNM) dosage given during the induction. The files of 86 consecutive adult ALL patients treated in our institution between 1974 and 1988 were reviewed. They received the same induction regimen based on Vincristine, DNM and Prednisone, consolidation with L-Asparaginase, central nervous system prophylaxis, and 3-year maintenance with 6-mercaptopurine and Methotrexate with periodic cycles of reinduction. We analysed the overall and disease-free survival (DFS) in relation to various prognostic factors, focusing on the dosage of DNM actually received during the induction period. Complete remission (CR) was achieved in 68 (79%) patients and the overall DFS was of 32 months (median follow-up 37 months); 22 patients (25.6%) are off-therapy and disease-free. The actual dosage of DNM received during induction turned out to be an independent DFS prognostic factor. In fact, patients who received more or less than 175 mg/sqm in induction had a median DFS of 44 and 12 months, respectively (p = 0.05). The plateau of DFS in the two groups was 44% and 21%, respectively. Similar data were found analyzing the dose-intensity (mg/sqm/week) of DNM given in induction. Our data suggest that the actual dosage of DNM given in induction plays a role in the long term DFS of adult ALL.

Detection of membrane and intracellular antigens by flow cytometry following ORTHO PermeaFix fixation.

In the present study, we explored the suitability of a new cell fixative (ORTHO PermeaFix, OPF) for the detection by flow cytometry of intracellular molecules while preserving the cell surface immunoreactivity, scatter features and morphology. The effect of OPF was investigated on whole blood of ten normal donors, and on separated blasts of 17 leukemic patients. OPF fixation for 45 min to 24 h maintained the morphology of lymphoid cells with minimal cellular distortion and scatter changes, and only slightly modified cell surface immunoreactivity. For at least 1 week following fixation, the cells were still suitable for immunostaining with monoclonal antibodies that recognize the main lymphoid populations. These included CD3, CD4 and CD8 for T-cell subsets, CD19 and CD16 for B lymphocytes and NK cells, and CD45 for leukocyte common antigen (LCA). The OPF fixation of leukemic cells allowed the simultaneous detection of nuclear TdT in conjunction with membrane CD19, and with membrane and/or cytoplasmic CD22 in common-ALL, as well as with cytoplasmic CD3 in T-ALL cases. Our findings suggest that with the introduction of this new fixative into the routine laboratory service, a number of convenient and practical arrangements can be made which increase the efficiency of immunodiagnosis. Small laboratories with no inhouse flow-cytometric facilities can now accumulate OPF-treated whole blood samples for at least 3-4 days and send these to reference laboratories. In addition, the immunodiagnosis of acute leukemia is greatly facilitated by combination staining for membrane and intracellular antigens both at diagnosis and when the analysis of minority populations is warranted for detecting minimal disease.

Estimated 6-year event-free survival of 55% in 60 consecutive adult acute lymphoblastic leukemia patients treated with an intensive phase II protocol based on high induction dose of daunorubicin.

On the basis of a previous experience suggesting that daunorubicin dose in induction was an independent prognostic factor in adult ALL, we designed a chemotherapeutic regimen (ALLVR589) characterized by high doses of daunorubicin (270 mg/m2) in induction and by high-dose Ara-C in post-remission. The protocol was otherwise conventional: induction and post-remission therapy were followed by chemo-radio prophylaxis of the central nervous system (CNS) and periodical reinductions over a 3-year maintenance period. Sixty consecutive patients (male 42, female 18, median age 34 years, range 14-71; B-lineage, 35; T-lineage, 25; Ph' and bcr/abl positive, 7) recruited between 1989 and 1996, were evaluated for treatment outcome. Complete remissions were 56 (93%), one patient had refractory disease, early deaths were five (8%); 19/56 (34%) patients relapsed, five of whom were Ph'+. Median time to relapse was 11 months (range 3-47); 68% of relapses occurred within 12 months from CR. No CNS relapses were observed. After a median follow-up of 44 months (1-100), 33/60 (55%) patients remain event-free; 23/60 (38%) are off-therapy in continuous CR (median follow-up from diagnosis: 63 months; range 38-100). These results suggest that increasing DNM dosage in induction is one of the possible approaches to improve the outcome of adult ALL by decreasing the relapse occurrence.

Immune response to Hepatitis B vaccine in patients with celiac disease: A systematic review and meta-analysis.

It is debated whether patients with celiac disease (CD) have non-protective antibody responses to HBV vaccination more frequently than non-affected subjects. To perform a literature review and meta-analysis on protective response to HBV vaccination in CD patients. RCTs and observational controlled studies were eligible. Outcome of interest was an anti-HBs (HBsAb) titer ≥ 10 IU/L after last vaccine dose. Comparative index was rate ratio (RR). Heterogeneity between studies was addressed and funnel plots were analyzed. Meta-regression models were applied to investigate effect size due to study-specific variables. Twelve retrospective studies on a total of 1,447 participants and 4 prospective studies on 184 subjects were selected. The RR was 0.732 (95% C.I.: 0.664-0.808) and 0.777 (95% C.I.: 0.629-0.960) in the prospective and retrospective studies, respectively. The I(2), indicating heterogeneity, was 51.1% in retrospective, 39.8% in prospective studies. Non-protective antibody responses occurred more frequently in patients than controls. Due to limitations in the available studies, additional trials to evaluate post-vaccination HBsAb titer in CD patients are needed.

Selenium dependent glutathione peroxidase: a physiological regulatory system for platelet function.

In human platelets the selenoenzyme glutathione peroxidase (GSH-Px) acts as a scavenger of the peroxides generated during the burst of arachidonic acid (AA) metabolism. Such a mechanism inhibits the biosynthesis of both thromboxane A2 (TXA2) and lipoxygenase products. The same mechanism is not effective on the prostacyclin (PGI2) biosynthesis from cultured endothelial cells. In order to evaluate this effect in vivo, besides in vitro, we activated the enzyme in eight normal volunteers by increasing their daily Se intake for 8 weeks, monitoring: platelet GSH-Px activity, platelet aggregation induced by AA and U 44069, and concurrent malondialdehyde (MDA) and thromboxane B2 (TXB2) production, urinary excretion of renal and systemic TXA2 and PGI2 metabolites, platelet enzyme activities of the hexose monophosphate pathway and glutathione content, platelet adenine nucleotides, bleeding time, plasma Se concentration. We found: a) progressive platelet GSH-Px activation by Se paralleling an enhancement of platelet aggregation threshold values for AA, but not for U 44069; b) concurrent inhibition of platelet biosynthesis of TXA2 both in vitro and in vivo while the biosynthesis of systemic prostacyclin was unaffected; c) a progressive increase in the bleeding time, unmodified by aspirin. In conclusion, we believe that Se-dependent GSH-Px represents a physiological mechanism regulating the biosynthesis of prostanoids with implications in platelet function and that a Se dietary supplement might be considered in the prevention of arterial thrombosis.

Primary extranodal lymphomas of Waldeyer's ring, stage IE and IIE.

We reviewed 45 cases of Waldeyer's ring lymphomas (25 stage IE, 20 IIE): 73% had high-grade histology according to Kiel's classification. Fourteen patients received radiotherapy alone and 31 chemotherapy, combined with radiotherapy in 28. Complete remission rate was 95% and relapse rate 32%. At 8 years overall disease-related survival (DRS) and event-free survival (EFS) were 69% and 57% respectively. Combined treatment provided both significantly better DRS (82% vs 42%) and EFS (76% vs 25%) than radiotherapy alone. Most of the patients with high-grade histology (26/33) received the combined treatment and this subgroup achieved a long-term EFS of 78%. Both DRS and EFS were also significantly longer in patients under 60. At multivariate analysis favorable prognostic factors were lower age for DRS and combined treatment for EFS.

Hyperferritinaemia without iron overload: pathogenic and therapeutic implications.

It is not unusual to meet increased levels of ferritinaemia in patients apparently healthy. Among other causes of hyperferritinaemia, recently was described the Hereditary Hyperferritinemia Cataract Syndrome, a genetic condition characterized by increased serum ferritin values without iron overload and bilateral nuclear cataract, both of early onset. It has been demonstrated that single or double point mutations or deletions in the stem-loop structure of the iron regulatory element (I.R.E.) located in the 5 untranslated regions of the ferritin L-subunit gene (19q13.1) are responsible for the upregulation of ferritin. This overexpression only for the L-chain gives rise to typical piles in several tissues. When this altered ferritin accumulates in lens it causes bilateral nuclear cataracts, that is the peculiar sign of this syndrome. It is essential to differentiate true iron overload from Hereditary Hyperferritinaemia Cataract Syndrome (H.H.C.S.), because these patients rapidly develop iron deficient anaemia when venosectioned. Here we describe a case report about a 40 years old healthy female blood donor who presented isolated hyperferritinaemia without iron overload, in the absence of concomitant pathologies. Anamnestic, biochemical, instrumental and clinical investigations led us to diagnose H.H.C.S., a pathology first described in 1995. From 1995 to date about 40 cases concerning patients showing the characteristics of this syndrome from Europe, USA, and Australia were described. Biochemical, genetical and clinical investigations led finally to understand every matter of this pathology, providing conclusive and exhaustive explanations.

Improved prognosis of Pseudomonas aeruginosa bacteremia in 127 consecutive neutropenic patients with hematologic malignancies.

OBJECTIVES: Although decreasing in frequency, Pseudomonas aeruginosa bacteremia is still a major challenge for neutropenic cancer patients. In patients with hematologic malignancies, the prognosis of P. aeruginosa bacteremia is particularly poor due to the prolonged and severe neutropenia, mucosal damage, and other defects in immunity related both to the underlying disease and to the cytotoxic therapy. METHODS: To verify the outcome of P. aeruginosa bacteremia and to try to define possible prognostic factors, the authors reviewed the medical records of 127 consecutive episodes of P. aeruginosa bacteremia observed in the hematologic unit of the Verona University School of Medicine. RESULTS: Presence of pneumonia and septic shock, persistence and severity of neutropenia, delayed and inappropriate antibiotic therapy, and unresponsive underlying disease had negative impact on clinical outcome of P. aeruginosa bacteremia. CONCLUSIONS: With recognition of the risk factors and more careful management, the prognosis of P. aeruginosa bacteremia in neutropenic patients with hematologic malignancies has improved in recent years.

Acute leukemia and pregnancy. Case report.

In this case report we describe a case of acute myeloid leukemia (AML; FAB M4) diagnosed in a 27-year-old female at the 20th week of gestation. After informed consent, the patient chose to undergo anti-leukemic treatment without therapeutic abortion. Complete remission was obtained following standard chemotherapy for AML (doxorubicin, cytosin-arabinoside, 6-thioguanine). The patient successively underwent an autologous bone marrow transplant (ABMT). No fetal malformation was observed. Urgent cesarean section was necessary at the 29th gestational week because of the onset of foetal sufferance. Fourteen months after diagnosis and seven months after ABMT the patient died due to relapse of AML. The child is presently 3.5 year old and well. In our opinion, the care of a pregnant woman with acute leukemia is feasible and it needs a multi-specialist effort that is easier to be achieved in a tertiary care institution.

[Surgery and chemotherapy in the treatment of primary gastric lymphomas: case review]. / Chirurgia e chemioterapia nel trattamento dei linfomi gastrici primitivi: revisione casistica.

Fifty-seven patients with primary gastric non-Hodgkin's lymphoma are here reported. All our patients were treated with surgery as first step procedure. Thirty-six were treated in addition with chemotherapy (four of them with radiotherapy also). Thirty-eight were stage IE and nineteen IIE. According to the Working Formulation, 12 cases were classified as low, 25 intermediate and 20 high malignancy. 55 patients achieved a complete remission (96%) and only 6 relapsed (11%). The 10-year disease-related survival is 89%. Patients treated with combined surgery and chemotherapy were mainly a high risk group (high grade histologic subtype, stage IIE, incomplete resection). Nevertheless the survival of this group was similar to the group initially treated with surgery alone (p = 0.17) in which such unfavorable prognostic factors were not present. Stage, presence of residual tumor after surgery, sex and age did not statistically correlate with survival. Furthermore, there was not statistical difference among the various histological subgroups (p = 0.16). We stress the importance of cooperation among surgeons and oncologists in order to plan an appropriate treatment.

[Non-Hodgkin's lymphomas of the oromaxillofacial area. A clinical contribution]. / Linfomi non-Hodgkin della regione oro-maxillo-facciale. Contributo clinico.

The authors present a clinico-statistical review (January 1987-December 1994) of 19 patients with non-Hodgkin's lymphoma of the oro-maxillo-facial region, diagnosed in the Dentistry Department of the University of Verona in collaboration with the Haematology Department. Particular attention has been devoted to the localisation, symptomatology, diagnosis and histological typing of non-Hodgkin's lymphoma of the maxillofacial region, stressing the importance of diagnosis and staging, based on a multidisciplinary approach, in order to be able to plan the most appropriate therapeutic management of patients with the disease.

Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib.

Health-related quality of life (HRQOL) is an important goal of therapy for chronic myeloid leukemia (CML) patients treated with current molecular-targeted therapies. The main objective of this study was to investigate factors associated with long-term HRQOL outcomes of CML patients receiving imatinib. Analysis was performed on 422 CML patients recruited in an observational multicenter study. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Key socio-demographic and clinical data were investigated for their association with HRQOL outcomes. Chronic fatigue and social support were also investigated. Univariate and multivariate linear regression analyses were used to identify independent factors associated with HRQOL outcomes. Fatigue was the only variable showing an independent and consistent association across all physical and mental HRQOL outcomes (P<0.01). Differences between patients reporting low versus high fatigue levels were more than eight and seven times the magnitude of a clinically meaningful difference, respectively, for the role physical (Δ=70 points) and emotional scale (Δ=63 points) of the SF-36. Fatigue did not occur as an isolated symptom and was most highly correlated with musculoskeletal pain (r=0.511; P≤0.001) and muscular cramps (r=0.448; P≤0.001). Chronic fatigue is the major factor limiting HRQOL of CML patients receiving imatinib.

AIDS-related non-Hodgkin's lymphomas from an Italian area.

In a retrospective study, 42 (7.7%) of 545 patients with AIDS from a single area of Italy had non-Hodgkin's lymphoma (28 systemic and 14 primary central nervous system lymphomas). The improved outcome and survival of treated patients outlines the clinical benefit of antineoplastic treatment in selected cases.

Early lymphoid blastic crisis following major karyotypic conversion in a chronic myeloid leukemia patient treated with interferon-alpha.

A major karyotypic conversion following interferon-alpha treatment delays or prevents blastic crisis in patients with chronic myeloid leukemia. We report here a 12-year-old boy with Ph1+ chronic myeloid leukemia who, after achieving a major karyotypic conversion following 12 months interferon-alpha treatment, developed an early lymphoid blastic transformation 7 months later while still under interferon-alpha therapy. A number of possible explanations for this quite unexpected event are discussed.

Soluble forms of p55-IL-2R alpha, CD8, and CD30 molecules as markers of lymphoid cell activation in infectious mononucleosis.

BACKGROUND: Epstein-Barr virus (EBV) infection in infectious mononucleosis (IM) is associated with lymphocyte activation leading to the expansion of cells expressing activation-associated antigens. Most of these antigens are released as soluble molecules in vitro and in vivo. METHODS: We investigated the serum levels of the soluble forms of the CD8 (sCD8), p55-IL-2R alpha (sIL-2R alpha), and CD30 (sCD30) molecules in 55 patients following primary EBV infection. These data were compared with the phenotypic pattern of circulating lymphoid subsets. RESULTS: In all cases at presentation, lymphocytosis, mainly characterized by the expansion of a CD8+, HLA-DR+, p75-IL-2R beta+, p55-IL-2R alpha- population, was associated with high levels of the investigated soluble molecules. Their mean values (+/- SD) were: 17,172 +/- 12,885 U/mL for sCD8 (vs 334 +/- 95 in controls), 2,922 +/- 2,813 U/mL for sIL-2R alpha (vs 331 +/- 115 in controls), and 477 +/- 451 U/mL for sCD30 (vs 4.9 +/- 6.4 in controls). Follow-up study (15 cases, up to 60 days) showed a progressive decline of all soluble molecules, associated with a reduction of activated CD8+/HLA-DR+/p75-IL-2R beta+ T-cells. By the 30th day, values of sIL-2R alpha and sCD30 (729 +/- 333 U/mL and 20 +/- 21 U/mL, respectively) were only slightly higher than in normal controls, whereas sCD8 levels remained consistently higher (1,777 +/- 1,385 U/mL, p < .001). CONCLUSIONS: sCD8, sIL-2Ra and sCD30 serum levels in IM reflect the total bulk and/or the activation-related events of infected and reactive cells. The variations in these soluble molecules during the follow-up provide useful information on the in vivo biological modifications occurring after EBV infection.

A comparative analysis of three different techniques for the detection of breast cancer cells in bone marrow.

Three different methods, morphologic, immunocytochemic, and fluorescence activated cell sorter (FC) analysis, were compared with respect to their efficiency in detecting breast cancer cells in bone marrow. In the first series of experiments, the three techniques were compared using bone marrow cells artificially mixed with a known amount of breast cancer cells, whereas in a second series bone marrow from breast cancer patients with bone metastases were used. The following results were obtained: When mixtures of the first series were analyzed, FC analysis detected from 1% to 10% of breast cancer cells in bone marrow (0.2% was a border line value), the morphologic method detected from 0.05% to 10%, and the immunocytochemic method, which was clearly superior, detected breast cancer cells in all mixtures (from 0.00025% to 10%). It was noted that, with both the morphologic and immunocytochemic methods, the percentage of breast cancer cells detected was 2 to 360 times higher than the percentage of added cells, and enrichment was inversely proportional to the percentage of added cells. This result could be a result of different separation of cells during centrifugation due to the different density of breast cancer cells. The superiority of the immunocytochemic method was confirmed in the second series of experiments.