Autoimmunity and auto-immune syndromes associated with and preceding the development of lymphoproliferative disorders.

In this report the association of autoimmunity and autoimmune syndromes with lymphoproliferative disorders (LPD) is described in 15 patients. Non-Hodgkin's lymphoma (NHL) developed in 10 patients, Hodgkin's disease (HD) in 3 and chronic lymphocytic leukemia (CLL) in two. In most instances clinical and laboratory phenomena preceded the development/diagnosis of these disorders. Manifestations ranged from the presence of autoantibodies in the serum to the presence of both ill defined or incomplete autoimmune syndromes including cold urticaria, Raynaud's phenomenon, cold agglutinin disease, thyroiditis, nephrotic syndrome and vasculitis to typical systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and even one of scleroderma. It is suggested that in some patients (in)complete clinical manifestations of autoimmunity may precede the development of lymphoid neoplasias. The link between autoimmunity and lymphoproliferative disorders is briefly discussed.

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.

Corynebacterium xerosis endocarditis.

Bacterial endocarditis due to Corynebacterium xerosis developed in a previously healthy person. Diphtheroid infection is a rare cause of endocarditis and, when present, it usually affects immunocompromised hosts or prosthetic valves. There are few reports of diphtheroid endocarditis on intact valves, and, to our knowledge, this is the first case in which the offending organism was identified as C xerosis. We call attention to the virulence of C xerosis in a person with no previous valvular disease.

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.

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 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.

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 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

Systemic lupus erythematosus and chronic lymphocytic leukemia: rare coexistence in three patients, with comments on pathogenesis.

We describe three patients with coexistent chronic lymphatic leukemia (CLL) and systemic lupus erythematosus (SLE). In two patients, the CLL was present before or coexistent with the SLE when the SLE was diagnosed, while in the third, the CLL developed 5 years after the diagnosis of SLE was first made. Although the association of autoimmune diseases and lymphoproliferative disorders is well established, only a few patients with coexistent CLL and concomitant SLE have been reported. The possible pathogenesis of this rare association is discussed.

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.

Treatment of chronic myeloid leukemia with interferon alpha (Roferon): results of the Israeli Study Group on CML.

Thirty patients with chronic myeloid leukemia from 11 Israeli medical centers entered this study. Their ages ranged from 16-65 (median 41) and time from diagnosis to treatment was 1-16 months (median 4 months). After cytoreductive therapy with hydroxyurea (22 patients) or busulphan (8 patients), patients received 9 million units/day of recombinant interferon alpha-2 alpha (Roferon A) subcutaneously. Side effects included arthralgia or low back pain in 7 patients, thrombocytopenia in 9, weight loss in four, neurologic disturbances in 4 and leukopenia in 3 cases. Seventeen patients achieved complete hematologic remission (CHR) and 6 partial hematologic remission (PHR). Six patients achieved major cytogenetic response, 4 of them lost all Ph1 chromosome positive cells and 4 had minimal cytogenetic response. Frequency of relapse was high: 8 patients with CHR and 6 with PHR relapsed, but patients with major cytogenetic response did not relapse. Patients who had received prior therapy with busulphan had a higher remission rate but a lower quality of cytogenetic response. Escalation of Roferon to 12 million units per day in relapsing or nonresponding patients induced PHR in 2/7. Neutralizing anti-interferon antibodies occurred in 7 relapsing or nonresponding patients. The cytoreductive induction with hydroxyurea enhanced the hematologic remissions to a median of 6 weeks. Further studies should define the role of combination therapy in order to improve response and prevent relapses.

Anaplastic B-cell (Ki-1) lymphoma developing in a patient with polycythemia vera.

The association of lymphoproliferative disorders and polycythemia vera (PV) is extremely rare. Here we report a patient with PV who developed anaplastic B-cell (Ki-1) non-Hodgkin's lymphoma (NHL). The rare occurrence of lymphoproliferative disorder in the course of PV, may indicate that in a minority of patients, clonal expansion of an abnormal pluripotent haemopoetic stem cell could be responsible for both the PV and the NHL.

Chronic Lymphocytic Leukemia in Young Adults: Report of Six Cases Under the Age of 30 Years.

We describe six rare patients with B-type CLL under the age of 30 years. All were males and four showed a relatively aggressive clinical course requiring initial chemotherapy at an early stage of their disease. Four of the six patients developed prominent generalized lymphadenopathy accompanied by splenomegaly and a rapid increase in the peripheral blood lymphocyte count or a doubling time of less than 12 months and were symptomatic. Of the six cases, one still has Stage A (0) disease, 16 months after diagnosis and has not yet been treated, while another 29 year old male, initially stage C (3) at diagnosis, progressed rapidly, despite chemotherapy and died after 42 months. Of the remaining four patients all responded well to treatment initially, however one 24 year old male has progressed rapidly from stage A (2) to Stage B (2), 14 months after initial response to chlorambucil and prednisone. Two patients remain in Stage A (0), two and eight years respectively after chemotherapy; while the patient with the longest follow up is currently 39 years old in good partial remission with Stage A (0) disease ten years after initial diagnosis, having responded well to Fludarabine, following a major flare up of his disease recently. The rare phenomenon of young patients with CLL is reviewed and management options relating to new therapeutic approaches for this sub-population of young patients are discussed.

Late Relapse in Hodgkin's Disease: Report of Five Cases and a Review of the Literature.

During the past 15 years the treatment of Hodgkin's disease (HD) with chemo/radiotherapy has been shown to appreciably improve the long-term prognosis of patients, even those with more advanced disease. In the past it was accepted that the probability of primary relapse 5 years after achieving complete remission (CR) was small and a 5-year disease-free period was sufficient to be considered as a cure. During the past 15 years, however, more data has been published relating to late relapses in these patients after an initial "cure" has been achieved. This report briefly examines our own experience with five patients initially "cured" who relapsed 5 to 11 years after achieving CR and also reviews recent literature on the subject. The phenomenon of late relapse has thus become a more important issue in the management of patients with HD.

Splenic Rupture in Chronic Lymphoid Disorders: Possible Role of Opportunistic Infections.

Two patients with lymphoproliferative disorders, one with chronic lymphocytic leukemia and the other hairy cell leukemia, developed spontaneous rupture of the spleen during the course of their disease. In both cases, this rare complication occurred during systemic atypical infections with Salmonella Dublin and Candida tropicalis respectively. We suggest that severe infection may sometimes play a decisive role in the development of the splenic rupture in some patients who have splenomegaly due to these disorders.

Hodgkin's Lymphoma: Results of ABVD Chemotherapy in 40 Patients with Advanced or Bulky Disease.

During 1980-1986, 40 patients with advanced Hodgkin's disease or bulky disease were treated with six cycles of ABVD chemotherapy, and adjuvant radiotherapy was added to sites of bulky disease when required. Twenty-seven of the 40 patients (67.5%) were treated with ABVD as primary therapy and 13 (32.5%) received it as salvage therapy after initial failure. Twenty-seven patients (67.5%) had advanced stages 3 or 4 disease, while 13 (32.5%) had stage 2 with bulky mediastinal disease (more than 30% chest diameter). Only 7.5 % of the patients had no response to ABVD while 75% achieved CR and 17.5% PR. Seventy-four per cent of the patients with advanced stages 3 and 4 achieved CR and 15% reached PR, with only two failures to ABVD. The median survival for the entire group is currently more than 41 months, with a median disease-free interval (DFI) of 27.5 months for all treated patients. The results compare favorably with those reported from other major centers dealing with larger series of patients. New approaches for future treatment employing alternating shorter courses of MOPP/ABV are discussed, and the importance of radiotherapy for bulky disease is emphasized.

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.

Primary lymphoma of the parotid gland: a report of twelve cases with a review of the literature.

Primary extranodal lymphoma of the salivary gland is an extremely rare disease. In this report we describe twelve cases of primary lymphoma of the parotid gland seen at a single centre, and review the relevant literature. The 12 cases were treated in different departments and did not receive a uniform therapeutic approach. All three patients with Hodgkin's disease are still alive and two are in complete remission after initial radiotherapy. One of these cases developed stage 4 disease and had to receive combination chemotherapy subsequently. Of the 9 non-Hodgkin's lymphoma (NHL) patients, four had low grade NHL and 5 intermediate or high grade NHL. Of these, 2 died with disseminated disease. However, 6 are still alive and well from 1 to 5 years after therapy. These cases were treated with surgery alone, radiotherapy alone or combination chemotherapy with an anthracycline-bearing regimen. Consequently, we are unable to draw any conclusions relating the success of therapy in these cases, nor can we suggest therapeutic guidelines on the basis of this study alone. The treatment of parotid lymphoma is discussed briefly in the light of the available literature. In most cases, symptoms related to an enlarging mass in the parotid region, were evident. In the light of the above data, we suggest that, despite its rarity, lymphoma of the salivary gland should always be considered in the differential diagnosis of a parotid mass. No correlation between lymphoma and Sjogren's syndrome was noted in the present study.

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.

Acute abdomen due to granulocytic sarcoma of the terminal ileum.

A 57-year-old patient with chronic granulocytic leukemia in blast crisis and severe neutropenia is presented. This patient developed right sided peritonitis due to an isolated transmural granulocytic sarcoma of the terminal ileum. The affected segment was resected and the patient survived 4 more months. Thus, despite neutropenia, an aggressive surgical approach should be considered in a leukemic patient presenting with unexplained acute abdomen, since, as demonstrated here, a localized lesion which could not have otherwise been detected, was ultimately found and promptly resected.