'1-8 interferon inducible gene family': putative colon carcinoma-associated antigens.

D(b-/-)xbeta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/D(b)-beta2m single chain (HHD mice) are an effective biological tool to evaluate the antitumour cytotoxic T-lymphocyte response of known major histocompatibility-restricted peptide tumour-associated antigens, and to screen for putative unknown novel peptides. We utilised HHD lymphocytes to identify immunodominant epitopes of colon carcinoma overexpressed genes. We screened with HHD-derived lymphocytes over 500 HLA-A2.1-restricted peptides derived from colon carcinoma overexpressed genes. This procedure culminated in the identification of seven immunogenic peptides, three of these were derived from the 'human 1-8D gene from interferon inducible gene' (1-8D). The 1-8D gene was shown to be overexpressed in fresh tumour samples. The three 1-8D peptides were both antigenic and immunogenic in the HHD mice. The peptides induce cytotoxic T lymphocytes that were able to kill a colon carcinoma cell line HCT/HHD, in vitro and retard its growth in vivo. One of the peptides shared by all the 1-8 gene family primed efficiently normal human cytotoxic T lymphocyte precursors. These results highlight the 1-8D gene and its homologues as putative immunodominant tumour-associated antigens of colon carcinoma.

Malignant thymoma complicated by amegakaryocytic thrombocytopenic purpura.

We report the case of a 41-year-old man with malignant thymoma complicated by amegakaryocytic thrombocytopenia 10 years after diagnosis of myasthenia gravis. A bone marrow aspirate showed an absence of megakaryocytes with normal maturation and differentiation of myeloid precursors. Three months later, severe neutropenia occurred, and a bone marrow examination confirmed the diagnosis of severe aplastic anemia. Associations between thymoma and myasthenia gravis, between thymoma and pure red cell aplasia, and between thymoma and aplastic anemia are well documented. Amegakaryocytic thrombocytopenia is not a recognized paraneoplastic syndrome complicating thymoma. Amegakaryocytic thrombocytopenia complicating thymoma may be a very early presentation of impending aplastic anemia.

Variant Richter's syndrome: a rare case of classical Hodgkin's lymphoma developing in a patient with chronic lymphocytic leukemia treated with fludarabine.

We report a case of a 52-year-old male who developed classical Hodgkin's lymphoma (HL) four years after diagnosis of stage Rai II (Binet B) chronic lymphocytic leukemia (CLL). The patient was treated with fludarabine and cyclophosphamide with partial response. Subsequently, he presented with a 6-month history of weight loss and fatigue, and 6 weeks of fever, a progressively enlarged liver and elevated serum LDH level. An inguinal lymph node biopsy revealed both classical Hodgkin's lymphoma, nodular sclerosing type grade 2 and CLL. A bone marrow biopsy showed no Reed-Steinberg cells and an infiltrate composed of only scattered small lymphocytes consistent with CLL. Immuno-histochemical studies of the lymph node were consistent with both CLL and HL phenotypes. A cytogenic examination of the bone marrow revealed an abnormal karyotype (Y-) in 15% of the cell population. Treatment with MOPP/ABVD was started and fever subsided within 3 days. Our case is one of the very few descriptions of a rare Richter's variant of CLL with progression to HL in a CLL patient treated with fludarabine. Since fludarabine has become standard therapy in CLL such Richter's variant could be the result of therapy, an induced prolonged and severe immunosuppression. Clinicians should be aware of such association, which could become more frequent among CLL patients treated with purine analogs.

[An unusual coincidence of thrombotic thrombocytopenic purpura and pernicious anemia].

A 52 year old man was admitted for hospitalization due to dizziness and weakness that appeared in the previous 2 weeks. Anemia and thrombocytopenia, as well as elevated levels of lactic dehydrogenase, reticulocytosis and schistocytes on blood smear, all suggested thrombotic thrombocytopenic purpura. However, B12 deficiency was also diagnosed. The diagnosis of pernicious anemia was reassured by both fundic biopsy and the existence of antiparietal cells antibodies and anti-intrinsic cells antibodies. A few courses of plasmapheresis along with parenteral B12 stabilized his physical condition and he was released with no need for further treatment, and only required ambulatory follow-up.

Persistent paraneoplastic neurologic syndrome after successful therapy of Hodgkin's disease.

Paraneoplastic neurologic syndromes may develop in Hodgkin's disease (HD). We describe three young female patients with neurological disorders, not explained by other causes, preceding diagnosis or relapse of HD. The lack of response of the paraneoplastic syndrome to successful treatment of HD among our three patients emphasizes the poor prognosis of longstanding paraneoplastic neurologic symptoms in HD.

The heterogeneity of Castleman disease: report of five cases and review of the literature.

Castleman disease (CD; angiofollicular lymphoid hyperplasia) is a heterogeneous group of lymphoproliferative disorders of uncertain cause. Three histologic variants (hyaline vascular, plasma cell, and mixed) and two clinical types (localized and multicentric) of CD have been described. We report 5 cases of CD treated in our institute and review the literature about the management of this relatively rare disorder. Localized and multicentric CD may be different clinical disorders with overlapping histologic features. Localized disease generally presented with a single enlarged lymph node or widening of the mediastinum, whereas multicentric disease is a systemic lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, constitutional symptoms, anemia, hypoalbuminemia, and hypergammaglobulinemia. Unlike the localized type, for which surgical excision is curative regardless of the histologic type, multicentric disease often necessitates aggressive systemic therapy and portends a poorer outcome.

Clinical implications of fluorescence in situ hybridization analysis in 13 chronic myeloid leukemia cases: Ph-negative and variant Ph-positive.

Thirteen chronic myeloid leukemia (CML) patients, 10 with variant Philadelphia (Ph) translocations and 3 Ph negative cases, were analyzed by fluorescence in situ hybridization (FISH) with the use of BCR and ABL cosmid probes and a chromosome 22 painting probe. In the variant Ph translocations, the BCR-ABL fusion gene was located on the Ph chromosome; in 1 CML Ph-negative patient, the BCR-ABL fusion gene was located on the Ph chromosome; and, in 2 patients, it was located on chromosome 9. The chromosome 22 painting probe was detected on the third-party chromosome of the variant translocation, and in none of the variant translocations was there any detectable signal on chromosome 9. In CML patients with clonal evolution of a simple Ph, a signal of the chromosome 22 painting probe was detected on the der(9) of the Ph translocation. It was concluded that the variant Ph translocations evolved simultaneously in a three-way rearrangement. The clinical parameters of the 13 patients were similar to those of a large group of CML patients with a simple Ph translocation. It is suggested that, to determine the prognosis of CML patients with a complex karyotype, FISH analysis with a chromosome 22 painting probe be performed.

The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus.

We have recently reported that dietary fish oil supplementation (n-3) polyunsaturated fatty acid (PUFA) led to a reduction in blood pressure (BP) and serum triglycerides (TG), in addition to the normalization of the hypercoagulable state in subjects with obesity, hypertension and dyslipidemia without diabetes mellitus (OHD-DM). The aim of the present study was to explore the mechanism of this amelioration by comparing the previous results to those obtained from 19 subjects who, in addition to the conditions described above, also suffer from diabetes mellitus (OHD+DM) and proteinuria. In both the non-diabetic and diabetic groups, a similar reduction was observed in BP (from 158.7/80.8 to 146/72.9 mmHg, and from 157.6/83.2 to 141.9/75.6 mmHg, respectively, P<0.001) and TG levels (from 159.2 to 108.0 mg/dl and from 208.7 to 153.1 mg/dl, respectively, P<0.001). However, a favorable reduction in hemostasis parameters (platelet aggregation on extracellular matrix and (alpha2-antiplasmin) was only seen among the nondiabetic patients (from 12.1+/-4.9 to 4.2+/-3.2%, P<0.001). This difference may stem from a less efficient exchange between n-3 and n-6 PUFA in serum phospholipid of the OHD+DM patients. Overall, this 13-day fasting/refeeding method developed by us has proven to cause the rapid exchange of arachidonic acid for eicosapentaenoic acid. It appears to be an effective regimen for the reduction of cardiovascular risk factors (BP, TG and hemostatic variables) in OHD-DM patients and to a lesser extent in OHD+DM patients.

Multiple chromosomal abnormalities in fulminant anaplastic myeloma.

We describe a 58-year-old woman with anaplastic multiple myeloma and multiple chromosomal abnormalities. Her karyotype showed extreme hyperploidy with 77 chromosomes. Some of the aberrations were typical of multiple myeloma (+3, +5, +15, +19, +21, t(11;14)(q13;q32)), others were characteristic of the aggressive anaplastic myeloma (+8), t(11;14)(q13;q32), while three chromosomal abnormalities (t(11;20)(p11;q13); t(4;7)(q31;q11); and t(14;20)(q24;q13)) have not been, to the best of our knowledge, described previously in the literature. The fulminant course of the disease confirms the poor prognosis of multiple karyotypic abnormalities in myeloma.

Hypocomplementemia in multiple myeloma.

We report the results of a prospective study of the complement system in a cohort of 22 multiple myeloma patients: 11 women and 11 men, median age 66 years. There were 10 IgG, 8 IgA, 2 IgM and 2 light chain myeloma patients. Seven were in stage 1, 3 in stage 2 and 12 in stage 3. The serum complement component levels of the three pathways were measured in all patients and compared to normal values of 29 healthy controls. We found a depleted common pathway in 21 patients, and deficient alternative and terminal pathways in 6 patients. There was no difference in the complement profile of myeloma patients in the advanced or early stages of the disease. IgG and IgA myeloma patients had a similar complement profile. Nine patients, 7 with advanced disease, developed 17 infectious episodes. Most of these patients had a deficient classical pathway, but normal alternative and terminal pathways. This profile was not different from the complement system observed in patients without infectious complications. Activation of the three pathways of the complement system was evaluated in all 22 patients. The classical and alternative pathways were activated in most patients in early and late stages, but the terminal pathway (C5-C9) was more frequently activated in the later stages (7 of 12 patients) that in the earlier stages (1 of 10). We conclude that the complement system is deficient in multiple myeloma, most probably because of activation of the system, although no correlation could be demonstrated between the complement system and the clinical manifestations of the disease.

Study of fibrinolytic parameters in different types of polycythemia.

Polycythemia vera (PV) is a myeloproliferative disorder characterized by thrombotic and, less often, bleeding complications. Many mechanisms have been advanced to explain the occurrence of these complications, none of them satisfactory. We examined a cohort of 27 patients with PV, secondary erythrocytosis, and essential thrombocythemia for coagulation and fibrinolytic parameters, including euglobulin lysis test, D-dimer, and alpha2 antiplasmin. Ten of the 27 patients developed one or more thrombotic complications during the study. We found no clinical correlation between the studied parameters and the complications. Three patients, one of each group, with elevated serum alpha2 antiplasmin levels, developed severe arterial or venous thromboses.

Fatal chronic relapsing thrombotic thrombocytopenic purpura following autologous bone marrow transplantation for chronic myeloid leukemia.

Thrombotic thrombocytopenic purpura (TTP) is a severe and potentially fatal syndrome increasingly reported shortly after allogeneic bone marrow transplantation. We report a 49-year-old patient who developed a recurrent and ultimately fatal form of TTP late after autotransplant for chronic myeloid leukemia.

The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives.

The present study was aimed at analyzing the existence of an impaired complement system in CLL patients. For this purpose, the serum levels of the serum complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, C9, Factor B and properdin were repeatedly evaluated by means of radial immunodiffusion assay in 26 CLL patients over a period of 2 years. At the time of diagnosis, 18 of the 26 CLL patients showed low serum levels in at least one of these complement proteins as compared to a group of sex- and age-matched healthy subjects (P < 0.0001). Complement defects affected either the classical and/or the alternative pathway components, and in some case low levels of late components (C5-C9) were also observed. A reduced level of properdin was the most frequent abnormality (11/18). The presence of such abnormalities were correlated with the stage of the disease, and they were found in 100% of the patients (11) in advanced stages (Rai II-IV), and in 40% of patients (15) in early stages (0-1) (P < 0.004). Severe infections occurred in five patients; four of them were in advanced stages of the disease and had decreased levels of at least one complement component, whereas the remaining patient was in an early stage and had normal levels of complement components. These data support the notion that an impaired complement system might be involved in the pathophysiology of CLL and its infectious complications. Although more work is needed to sustain this hypothesis, we discuss the possibility on the basis of data obtained in the first-degree relatives of CLL patients, that in some CLL patients the complement deficit might reflect a genetic predisposition.

Repeated fasting and refeeding with 20:5, n-3 eicosapentaenoic acid (EPA): a novel approach for rapid fatty acid exchange and its effect on blood pressure, plasma lipids and hemostasis.

Twenty hypertensive subjects participated in three clinical trials of 13 days each, to examine the effects of Alsepa fish oil [20:5, n-3 eicosapentaenoic acid (EPA) 180 mg, and 22:6 n-3 docosahexaenoic acid (DHA) 120 mg] on n-3 for n-6 polyunsaturated fatty acids (PUFA) exchange on serum phospholipids, blood pressure (BP), triglycerides (TG) and primary hemostasis. After 13 days, plasma phospholipids showed an increase in sigma n-3 (EPA and DHA) from 2.0 to 5.9% (P < 0.01), and a decrease in sigma n-6 (arachidonic acid and linoleic acid) from 29.8 to 22.6% (P < 0.01). A concomitantly significant reduction in systolic BP (SBP) (158.7 +/- 23.8 mm Hg to 146.5 +/- 17.0 mm Hg, P = 0.04), and diastolic BP (DBP) (80.8 +/- 8.4 mm Hg to 72.9 +/- 14.9 mm Hg, P = 0.04) as well as a significant decrease in platelet adhesion and aggregation on extra cellular matrix measured as a percentage of surface coverage (11.9 +/- 4.8% to 4.2 +/- 3.2%, P = 0.0001) was observed. In addition, a significant reduction in baseline dependent TG was observed; the higher the baseline level TG, the more pronounced the reduction (average 159.2 +/- 74.6 mg% to 108.0 +/- 46.1 mg%, P = 0.001). No change was observed in total cholesterol, high and low density lipoprotein (HDL, LDL), platelet and fibrinogen. Repeated fasting and refeeding with fish oil facilitated plasma exchange of n-3 for n-6 PUFA, improved BP, clinical metabolic parameters and lowered platelet reactivity in the vessel wall (primary hemostasis). In severe and life-threatening situations, the beneficial effects of fish oil should be considered for rapid exchange of n-3 for n-6 PUFA. In this study we describe a novel approach for rapid fatty acid exchange by fasting/refeeding with fish oil supplementation, as well as improved BP, plasma lipids and primary hemostasis. Further research is required on the therapeutic use of fish oils and the physiological mechanisms involved in fatty acid exchange.

A prospective cohort study of the effect of vincristine on audition.

We conducted a prospective cohort study of the possible ototoxic effect of vincristine among patients treated for lymphoproliferative malignancies. No deleterious effect of moderate doses of vincristine on pure tone audiometry for air and bone conduction and on speech audiometry could be found. Nevertheless, the isolated finding of sensorineural hearing loss in the only patient who received a high dose of vincristine raises the issue of ototoxicity as a possible dose-related and dose-limiting side effect of vincristine.

Non-Hodgkin's lymphoma presenting with amegakaryocytic thrombocytopenic purpura.

A 91-year-old patient was diagnosed with amegakaryocytic thrombocytopenic purpura (AATP) as a presenting symptom for CD5-positive B cell non-Hodgkin's lymphoma. Lymphoma is another condition that should be considered in the differential diagnosis of AATP.

The complement system in chronic lymphocytic leukemia: a possible role in autoimmune manifestations.

We describe the complement system of three CLL patients who developed autoimmune complications in the course of their disease. The complement profile was pathological in both CLL patients with active autoimmune diseases, while it showed no deficiency in the patient with quiescent autoimmunity. The complement profile could be an early marker for development of autoimmunity in CLL patients