Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study).

It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer's Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

Development of JAK2V617F-positive polycythemia vera after chemotherapy-induced remission of primary central nervous system diffuse large B cell non-Hodgkin's lymphoma: a case report and review of the literature.

The coexistence or the development of Philadelphia chromosome-negative myeloproliferative neoplasms after a lymphoproliferative disease in the same patient is an extremely rare event. We report the case of a 72-year-old man who developed JAK2V617F polycythemia vera 3 years after the diagnosis and treatment of primary diffuse large B cell non-Hodgkin's lymphoma of the central nervous system. We also review the literature regarding the pathogenesis underlying the association of myeloproliferative and lymphoproliferative chronic disorders.

Primary plasma cell leukemia: a retrospective multicenter study of 73 patients.

BACKGROUND: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. PATIENTS AND METHODS: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). RESULTS: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. CONCLUSIONS: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes.

Management of poor peripheral blood stem cell mobilization: incidence, predictive factors, alternative strategies and outcome. A retrospective analysis on 2177 patients from three major Italian institutions.

CD34+ peripheral blood hematopoietic stem cells (HSC) are usually collected following mobilization therapy accomplished by using growth factors (GF) such as rHuG-CSF or rHuGM-CSF with or without chemotherapy. A target dose of yielded CD34+ is usually prescribed by the attending physician depending on different protocols, which may include single or double transplantation. HSC collection usually is performed when at least 20 CD34+ HSC/microL are detected by means of flow cytometry. A cumulative dose of at least 2 x 10(6)/Kg/bw CD34+ HSC has been considered as the threshold to allow a prompt and persistent hematopoietic recovery. Unfortunately, this goal is not achieved by the totality of patients undergoing mobilization regimen. In fact, 5-46% of patients who underwent mobilization therapy fail HSC collection due to very low peripheral blood HSC CD34+ count. Patients' characteristics, including age, sex, stage of the underlying disease (complete or partial remission), diagnosis, previously administered radio/chemotherapy regimens, time-lapse from last chemotherapy before mobilization and mobilization schedule (including dose of GF) were considered as possibly predictive of poor or failed mobilization. We performed a retrospective analysis in 2177 patients from three large Italian academic institutions to assess the incidence of poor mobilizers within our patients' series. Therefore, a patient who fails a first mobilization (and when an HLA-compatible related on unrelated donor is not available) could undergo a second attempt either with different mobilization schedule or by using different GF, such as stem cell factor, growth hormone (GH), or more recently newly introduced drugs such as AMD3100, alone or in combination with rHuG- or -rHuGM-CSF. Thus, we investigated the fate of those who failed a first mobilization and subsequently underwent a second attempt or alternative therapeutic approaches.

Venous thromboembolism and cancer: guidelines of the Italian Association of Medical Oncology (AIOM).

Thromboembolic complications represent one of the most important cause of morbidity and mortality in cancer patients. Although several data have been published demonstrating the strong association between cancer and venous thromboembolism (VTE), there is poor perception, among oncologists, of the level of risk of thrombosis and of relevance of managing VTE in these patients. The Associazione Italiana di Oncologia Medica (AIOM) has provided some recommendations to direct clinical practice according to evidence-based data concerning cancer and VTE. In fact, we conducted an extensive literature review (1996-2005) to produce evidence-based recommendations to improve perceptions of the magnitude of this risk among Italian medical and surgical oncologists and alert on the new approaches to prophylaxis and treatment of VTE in cancer patients. Levels of evidence are given according to a five-point rating system, and similarly for each key recommendation a five-point rating system suggests if the evidence is strong and indicate that the benefits do, or do not, outweigh risks and burden.

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry.

PURPOSE: To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND METHODS: Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death. RESULTS: Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkin's lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each). CONCLUSIONS: The present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

GAGs-potentiated inhibition of thrombin, factor Xa and plasmin in plasma and in a purified system containing antithrombin III - correlation with total charge density.

The ability of heparin and related glycosaminoglycans (GAGs) to accelerate the inhibition of thrombin, factor Xa and plasmin in plasma and in a purified system containing antithrombin III (At III) was studied using chromogenic peptide substrate assays. There was good correlation between the charge density of the mucopolysaccharides and the activities investigated. While the difference between potentiation of the antithrombin activity by GAGs in plasma and in the purified system was slight, the inhibition of factor Xa in plasma was more pronounced than in the presence of purified At III, indicating the mechanisms for GAGs-potentiated inhibition of thrombin and factor Xa are not identical. For the antiplasmin activity, there was a good correlation between the chemical structure and biological activity only in the pure system, confirming that the antithrombin-GAG complex plays a very limited role in the inactivation of plasmin in plasma.

Selective PF4 release in vitro induced by heparin and related glycosaminoglycans (GAGs)--correlation with beta-TG release and platelet aggregation.

We studied human platelet aggregation and beta-TG/PF4 release induced by heparin and related GAGs in vitro both in normal PRP and in PRP after aspirin. In our experimental conditions, heparin and related GAGs always caused PF4 release in vitro from normal platelets, whether or not there was measurable platelet aggregation in the aggregometer. Significant beta-TG release was induced only by the mucosal heparin preparation (which also induced platelet aggregation in some citrated PRP). Therefore, while beta-TG release in vitro seems to correlate with platelet aggregating activity of heparin, the selective PF4 release, caused by heparin and related GAGs also in conditions in which neither platelet aggregation nor beta-TG are measurable, is probably associated with the high affinity of PF4 for heparin. The degree of affinity of GAGs for PF4 (heparin greater than DeS greater than HS) seems to correlate with PF4 release. Moreover, the significant reduction in PF4 release in vitro after aspirin suggests that GAGs-induced PF4 release is related to a cyclooxygenase-dependent activation process.

Daunorubicin and platelet function.

The influence of Daunorubicin on some platelet functions in vitro was investigated, using different concentrations of the drug (0.01-0.02-0.04 microgram/ml). Daunorubicin was shown to inhibit Collagen and Thrombin induced platelet aggregation and the intensity of inhibition on both drug concentration and the time of preincubation. Daunorubicin was also shown to inhibit the release reaction, the platelet prostaglandin pathway and the availability platelet factor 3; the drug at concentrations for clinical use does not damage the platelet membrane, as is the case with the freezing and thawing test, in platelet uptake of 14C-serotonin and as confirmed by the electron microscope. When very high doses (0.16 mg) of Daunorubicin are used, lysis of the platelets can be observed and this is confirmed under the electron microscope by the presence of empty platelets with fractures at the level of the cytoplasmid membrane. Finally, Daunorubicin causes irreversible inhibition of reptilase clot-retraction, even if this is less severe than with Vincristine. Working with gel-filtered platelets, it would appear that the inhibition exercised by the drug on platelet reactions is not caused through modifications in Ca++ metabolism. The authors suggest that Daunorubicin, at the dosages used clinically, induces in vitro thrombocytopathy without damaging the cellular membrane as confirmed by the electron microscope. This impairment of platelet functions could play a part in hemorrhagic diathesis observed during Daunorubicin therapy.

Red blood cell support and alloimmunization rate against erythrocyte antigens in patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed red blood cell (RBC) support and alloimmunization rate in 218 consecutive patients - 128 from the Pediatric Department and 90 from the adult Hematology Department - undergoing hematopoietic stem cell transplantation (HSCT) between 1994 and 2000. In the pre-HSCT period, the pediatric patients undergoing auto-HSCT required more RBC support. In the post-HSCT period, pediatric patients transplanted with an unrelated donor required more RBC support (median 13.5 U/10 kg bw) than patients receiving HSCT from a related donor (median 6 U/10 kg bw) or from an autologous source (median 4 U/10 kg bw, P=0.0004). In the pre-HSCT period, 159 out of 218 patients (73%) received a total of 1843 RBC units, with an overall median of 9 U/patient over a median of 24 months (range 4-62); 10 patients (6%) developed a total of 12 alloantibodies, with an alloimmunization rate of 5.4/1000 RBC units. In the post-HSCT period, all but three patients were given a total of 2420 RBC units, with an overall median of 6 U/patient over a median of 4 months (range 1-18); all but one of the pre-existing alloantibodies disappeared and three patients (1%) developed new alloantibodies with an alloimmunization rate of 1.2/1000 RBC units. These newly produced alloantibodies (one anti-M and two anti-E) were detected at +58, +90 and +210 days after HSCT. These findings might suggest a different approach to alloantibody screening tests in patients receiving HSCT, with a subsequent reduction of costs and laboratory workload.

Primary shunt hyperbilirubinemia associated with Gilbert's syndrome.

A patient with primary shunt hyperbilirubinemia associated with Gilbert's syndrome is described. The laboratory findings of unconjugated hyperbilirubinemia, mild reticulocytosis, normoblastic erythroid hyperplasia of bone marrow, increased plasma iron turnover, and normal peripheral red blood cell survival were consistent with increased intramedullary hemolysis. Nevertheless, unconjugated bilirubin level exceeding 4 mg/100 mL, in the absence of appreciable anemia and of biochemical evidence of hepatic dysfunction, suggested the coexistence of defective hepatic bilirubin clearance. The mode of inheritance and the effect of fasting and phenobarbital on bilirubin concentrations were indicative of associated Gilbert's syndrome.

Cost-Effectiveness Analysis of Induction Regimens Containing Anthracyclines in Adult Acute Myelogenous Leukemia.

A cost-effectiveness analysis was performed to evaluate the impact on hospital costs of two alternative regimens, idarubicin + cytarabine and daunorubicin + cytarabine, in the induction treatment of newly-diagnosed patients with acute myeloid leukemia (AML). In evaluating the economic effects the perspectives of both hospital doctors and administrators were taken into account in order to achieve better value for money spent. For this study, the comparative results from four recently published randomized clinical studies were used as the source of clinical data. Data on the duration of hospitalization, hospital procedures and AML treatment costs were obtained from the patient records of two haematological centers. The idarubicin induction regimen appeared to be more cost-effective than that of daunorubicin in achieving complete remission, especially when costs are linked to response rate. Although several methodological issues in terms of economic evaluation still need to be solved, this type of study might offer a social contribution to the problem of the efficient allocation of resources in the health care sector.

Idarubicin in combination with cytarabine and VP-16 in the treatment of post myelodysplastic syndrome acute myeloblastic leukemia (MDS-AML).

Fifteen patients with a primary myelodysplastic syndrome (MDS) transformed into acute myeloblastic leukemia (AML) were treated with an intensive chemotherapy regimen containing idarubicin. A complete response (CR) was obtained in 10 patients (66.6%). In five of them this was achieved after a single course of chemotherapy. The median time to achieve a CR was 32 days (range 16-42). A partial remission (PR) was obtained in 2 patients after two induction courses of chemotherapy. One patient died during the first induction course following acute respiratory distress syndrome (ARDS) complication, whereas the chemotherapy regimen failed in 2 patients. A short interval between MDS and transformation into AML was associated with a better chance of achieving a CR. Age, karyotype, type of MDS, peripheral blood or bone marrow findings appeared to have no influence on the response to treatment. The median event free survival for patients who achieved CR was 15 months and the median actuarial survival 18 months. These preliminary results need to be confirmed in a multicentre prospective study comparing idarubicin with other anthracyclines.

Low-dose heparin in thoracic surgery: effect on blood coagulation and fibrinolysis system.

Plasma kallikrein, antithrombin III and antiplasmin were determined with chromogenic methods in 29 patients pre-, per- and post-operatively in a controlled, randomized study. 16 patients received calcium heparin, 5000 IU s. c. every 8 hr for 7 days, the first administration given 2 hr before surgical procedure. 13 control patients received saline. A significant reduction of kallikrein and antiplasmin in per- and post-operative periods was observed in the control patients compared with the heparin-treated patients, while there was a significant reduction of anti-thrombin III in the control patients compared with the treated patients only in the per-operative period. The results obtained suggest that activation of the coagulation and fibrinolysis system occurs in patients undergoing thoracic surgery, and that it is inhibited significantly by calcium heparin prophylaxis.

Immunoreactive calcitonin: a tumor marker for myelogenous leukemias.

In a series of 59 patients with chronic or acute myelogenous leukemia (CML, AML) we investigated whether circulating immunoreactive human calcitonin (i-hCT) levels correlate with diagnosis, response to therapy and clinical course. I-hCT was detectable in plasma samples of 88% of patients with CML in the chronic phase and in 100% of patients with CML in blastic transformation. In the AML patients, a significant relation was observed between the cytological subtype and i-hCT levels at diagnosis. In sequentially studied patients the i-hCT plasma concentration was related to the overall mass of leukemic cells, being lower when complete remission was achieved than at diagnosis and increasing at time of recurrence. These data suggest that circulating i-hCT levels can serve as a "tumor marker" in human myelogenous leukemias.

Effects of porcine calcitonin on human platelet fuction.

The effects of different doses of porcine calcitonin (pCT) were tested in vitro and in vivo. In vitro, pCT at a concentration ranging from 0.1 to 5 M. R. C. Units/ml induced a dose-dependent inhibition of ADP (1.2 microM) and collagen- (2 micrograms/ml) induced platelet aggregation, showing a prevalent action on the second wave of ADP-induced aggregation and causing prolongation of the lag time and reduction of both maximum aggregation and slope in collagen-induced aggregation. 45Ca uptake by platelets in the presence of the ionophore A23187 and 14C-serotonin release were also inhibited in a dose-related fashion, using concentrations ranging from 1 to 10 M. R. C. Units of pCT. The in vivo tests, performed before and after a 7-day treatment with 2 different doses of pCT (1 and 160 M. R. C. Units/daily, i. m.) confirmed the inhibitory effect of pCT on ADP- and collagen-induced platelet aggregation. It should be stressed that the effect of 1 unit was stronger than that of 160 units. It is therefore postulated that in vitro and in vivo effects of pCT on platelet functions probably depend on different mechanisms of action.

Defibrotide in recurrent thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a common illness characterized by platelet thrombi within the microvascularization. In its natural course, this disease has had a mortality rate of 90%. Plasma infusion or exchange achieved a survival rate of 70% to 90%. However, 10% to 30% of patients surviving the initial TTP episode relapse at regular intervals. The treatment of recurrent forms of the disease remains a challenge; several approaches have been shown to induce medium to long term remissions. We describe a patient with recurrent TTP whose disease remitted after administration of defibrotide.

Role of granulocyte colony-stimulating factor in relapsed/resistant intermediate and high-grade non-Hodgkin's lymphoma patients treated with the E-SHAP regimen.

AIMS AND BACKGROUND: The study assessed the role and potential benefit of rhG-CSF in reducing the frequency, duration and severity of neutropenia following cytotoxic chemotherapy according to the E-SHAP protocol and, at the same time in improving the response rate. METHODS: Twenty patients with resistant/relapsed intermediate or high-grade non-Hodgkin's lymphoma were treated with the E-SHAP regimen (etoposide+methyl prednisolone+high dose cytosine arabinoside and cisplatin), and in 15 of them, we administered rhG-CSF between chemotherapeutic courses. RESULTS: The 15 patients who received G-CSF after E-SHAP were neutropenic for a short time and experienced no febrile episodes or infective complications. In contrast, in the group (5 patients) who did not receive G-CSF, the WBC nadir was lower and the number of days with a neutrophil count below 1.0 x 10(9)/L was longer, with a greater risk of inferctious complications. Of the 15 patients, only one had a delay in chemotherapy administration, and the RDI was 95% in the 65% of patients who received G-CSF. Of 5 patients treated with chemotherapy alone, 4 had a delay and the RDI was over 95% in only one patient. We obtained a good overall response rate (70%) in the group who received G-CSF. In the historical group of 5 non-Hodgkin lymphoma patients, we observed only 1 partial response and 4 had progression of disease. CONCLUSIONS: Administration of G-CSF is associated with an acceleration of neutrophil recovery, indicating its potential to reduce the risk of infection. The use of G-CSF permitted us to administer intensive chemotherapy without delay and according to standard dosage, with an improved response rate.

CNS metastasis in ovarian cancer with microangiopathic hemolytic anemia associated with diffuse intravascular coagulation.

We present the case of a woman affected by ovarian cancer metastatic to multiple lymph node and the CNS. She was affected by hemorrhagic diathesis with microangiopathic alterations, whereas coagulopathy developed only after some days in coincidence with disease worsening. Our patient is probably one of those in which cancer leads to microangiopathy and coagulopathy by means of a tissue factor-like activity, a common event in mucin secretory tumors. Fibrinolytic activity was also increased in our patient as in others of the same type. The main aspect of this case report is metastasis to the CNS and to other multiple sites, which is quite uncommon in such cancers. We retain that tumor procoagulant activity could have played a role in this phenomenon.