Aristeidis Chaidos

Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients

Over the last few years, increased evidence has supported the role of iron dysregulation in the pathogenesis of multiple sclerosis (MS), as iron is essential for myelin formation and oxidative phosphorylation. We studied indices of iron metabolism, such as serum iron, ferritin, transferrin and soluble transferrin receptor (sTFR) levels in 27 MS patients. Seven patients had chronic progressive active disease (CP-A), six had chronic progressive stable (CP-S), ten had relapsing—remitting active (RR-A) and four had relapsing—remitting stable (RR-S) disease. sTFR levels were found to be significantly higher in CP-A (P=0.021) and RR-A (P= 0.004) patients than in controls. sTFR levels were also elevated in CP-S patients but did not reach significance (P=0.064). sTFR values in RR-S patients were comparable to those found in controls (P=0.31). Ferritin levels were significantly elevated only in CP-A patients (P= 0.002). Patients of the CP group had significantly higher ferritin values than the RR patients (P= 0.004). Haemoglobin values as well as iron and transferrin levels were within normal limits in all patients. In conclusion, the increased serum sTFR and ferritin levels in nonanaemic MS patients with active disease reflect the increased iron turnover. The mild elevation of sTFR levels in CP-S patients may indicate active inflammation with ongoing oxidative damage that is not detectable by history or examination.

Recombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis

Background: Patients with chronic idiopathic myelofibrosis (CIMF) usually present with anaemia. Treatment is often palliative and the majority of patients receive regular red blood cell (RBC) transfusions. Although recombinant human erythropoietin (rhu-EPO) has been proved effective for the treatment of anaemia in several chronic diseases, including haematological malignancies, its role in the treatment of the anaemia in CIMF is not well established. We report the beneficial effect of rhu-EPO administration in 20 patients with CIMF and discuss the parameters predicting favourable response. Patients: Twenty patients with CIMF (9 women and 11 men) regularly treated with supportive RBC transfusions were included in the study. The median age was 70 years (range 45–81 years). Rhu-EPO, 10,000 U, was given subcutaneously 3 times a week. The median duration of therapy was 83 months, ranging from 13 to 87 months. Results: Treatment was considered effective if haemoglobin levels increased over 2 g/dl within 12 weeks after enrolment or the RBC transfusion requirements were reduced by 50% within the same interval. Twelve patients (60%) responded to therapy. Responders were mainly female, had smaller spleen size (p = 0.024), low RBC transfusion requirements (≤1–2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and β2-microglobulin (β2-M) levels when compared with non-responders (p < 0.0001 and 0.00001, respectively). Treatment was well tolerated and none of the patients was withdrawn from the treatment protocol because of side effects. Conclusions: Rhu-EPO administration is an effective, safe and well-tolerated treatment for patients with CIMF and anaemia leading to a significant reduction in RBC transfusion requirements. Factors predicting favourable response are low endogenous EPO and β2-M serum levels and slight to moderate splenomegaly.

Treatment of β-Thalassemia Patients with Recombinant Human Erythropoietin: Effect on Transfusion Requirements and Soluble Adhesion Molecules

The most common single genetic disorder and a major public health issue in Greece and other Mediterranean countries is β-thalassemia. Current therapeutic approaches for homozygous β-thalassemia entail blood transfusions and iron chelation therapy with deferoxamine or deferiprone for preventing tissue hemosiderosis. Recently, much effort has focused on various inducers of fetal hemoglobin (HbF) such as recombinant human erythropoietin (rHuEPO), especially in β-thalassemia intermedia. Ten adult patients, 5 with β-thalassemia major and 5 with β-thalassemia intermedia, received 150 IU/kg rHuEPO (epoetin-α) subcutaneously three times a week. Seven patients were transfused every 14–30 days and 3 with β-thalassemia intermedia were only occasionally transfused. The minimum duration of treatment was 12 weeks in order to define if there was any response. Transfusion intervals were modified according to the rHuEPO response to maintain stable Hb values. Lower transfusion requirements were observed in 5 patients after rHuEPO treatment (p = 0.028). In the 3 non-transfused patients, Hb values increased, and the patients are still being treated and followed up for a period ranging from 14 weeks to 2 years. Two patients with thalassemia major discontinued treatment after 12 weeks, as they did not achieve any response regarding transfusion requirements or Hb values. Pretreatment serum transferrin receptor levels were higher than in controls (p < 0.001) and significantly increased following rHuEPO treatment (p = 0.027). Patients had higher serum endothelin-3, sICAM-1 and sE-selectin values before rHuEPO treatment compared to controls (p < 0.001, p < 0.001 and p = 0.016, respectively), but these values were not altered during treatment. HbF values presented a slight, non-significant increase. rHuEPO treatment has a beneficial effect in transfusion-dependent β-thalassemia patients. Although a slight increase in HbF levels was observed, other possible mechanisms are probably involved. None of our patients experienced thrombotic complications and a rise in blood pressure.

Treatment of Resistant/Relapsing Chronic Lymphocytic Leukemia with a Combination Regimen Containing Deoxycoformycin and Rituximab

Background: Patients with chronic lymphocytic leukemia (CLL) are sometimes resistant to treatment or relapse soon after the administration of the currently available frontline therapy including chlorambucil-prednisolone CHOP and fludarabine. We report the beneficial effect of an alternative chemotherapeutic regimen containing 2’-deoxycoformycin (pentostatin) and the monoclonal antibody anti-CD20 (rituximab) in 5 patients with resistant/relapsing CLL. Patients: Five patients (4 men and 1 woman) with CLL at stage C, according to Binet’s classification, were included in the therapeutic protocol. The median age of the patients was 76 years (range 57–84 years). Previous treatment consisted of chlorambucil-prednisolone, fludarabine, and CHOP. The current regimen comprised six 2-week cycles of pentostatin, 4 mg/m2 i.v., combined with four cycles of rituximab, in a dose of 375 mg/m2, every other week. Results: Three patients responded to therapy, 2 achieved complete remission and 1 a partial response. Two patients did not respond to treatment. Toxicity was mild and well tolerated. The median survival duration of the responders was 19 months. These promising results suggest that salvage therapy with a combination regimen including pentostatin and rituximab may have a beneficial effect in patients with resistant/relapsing CLL.

Incidence of apoptosis and cell proliferation in multiple myeloma: correlation with bcl-2 protein expression and serum levels of interleukin-6 (IL-6) and soluble IL-6 receptor.

Abstract: We evaluated the in vivo incidence of apoptosis and cell proliferation in multiple myeloma (MM) and investigated the correlation of both cellular events with histological tumour stage and grade, bcl‐2 protein expression, serum IL‐6 and sIL‐6R. Material and methods: The TUNEL method was used to assess apoptosis and immunohistochemistry to assess the expression of proliferating cell nuclear antigen (PCNA) and bcl‐2 protein in 30 bone marrow biopsy specimens. The apoptotic index (AI) and proliferative index (PI) were defined as the percentage of TUNEL and PCNA positive plasma cells, respectively. Results: The mean AI was 0.162% and the mean PI 27.44%. A positive correlation between AI and PI was found (r = 0.44, P = 0.017). PI was also correlated with tumour grade (P = 0.015). The mean bcl‐2 protein expression was 70% and did not correlate with AI or PI, but was higher in specimens taken at first diagnosis than in specimens taken after response to treatment (P = 0.035). The mean serum IL‐6 and sIL‐6R values were 9.43 pg mL−1 and 47.27 ng mL−1, respectively. These parameters did not correlate with AI or PI. Conclusions: The results indicate that MM might be among the malignancies with very low incidence of apoptosis. Proliferative activity increased in parallel with tumour histological grade. A positive correlation between apoptosis and proliferation was observed, but the incidence of these two cellular events seems not to be related to the bcl‐2 protein expression and the serum levels of IL‐6 and sIL‐6R.

Non-secretory multiple myeloma with involvement of the hand as initial manifestation.

A 78-year-old male patient with history of arterial hypertension, chronic obstructive pulmonary disease, and hypercholesterolemia presented with bone and joint pain of his left hand and a tumefaction of his left index finger (Figure 1a). Seven months before referring to our department he had a fracture of the metacarpal bone of his left second finger which was handled ina conservative way using a splint. The patient could not explain whether the fracture occurred spontaneously or after minor trauma. Several months after removing the splint, the fractured area was still painful and the finger became swollen. Because of the symptoms, he went through a new radiographic study of the hand which showed this time, various lytic lesions of the metacarpal bones, proximal and distal phalanges of the left hand (Figure 1b). Next, a fine-needle aspiration biopsy of the soft tissue was performed which showed increased cellularity with abundant neoplastic monoclonal plasma cells with eccentric nuclei, and occasionally binucleated, consistent with plasmacytoma. A bone marrow biopsy and a trephine aspirate did not reveal bone marrow plasmacytosis (only 2% of bone marrow cells were plasma cells). Moreover, he underwent skeletal bone survey including skull, spine, pelvis, humeri and femurs as required which revealed osteolysis of the pelvis. Magnetic resonance imaging of the spine was also performed which did not demonstrate other plasmacytomas or signs of cord compression. Quantification of serum immunoglobulins was normal [IgG: 11.2 gr/l, IgA: 1.78 gr/l, IgM: 0.56 gr/l, k: 2.1 gr/l, l: 1.21 gr/l, k/l ratio: 1.73, (normal values IgG: 8-17 gr/l, IgA: 0.85-4.9 gr/l, IgM: 0.5-3.7 gr/l, k: 2-4 gr/l, l: 1.1-2.4 gr/l, k/l: 1.35-2.65)] and protein electrophoresis and immunofixation in both serum and urine detected no monoclonal immunoglobulin supporting a diagnosis of a non-secretory myeloma according to pre-established criteria [1]. Initial laboratory values were normal with hemoglobin level of 16.2 gr/dl, white cell blood count 7.910/ml, platelets 134.000/ml, ESR 1 mm/h, CRP 2 mg/dl, creatinine 1.2 mg/dl, urea 46 mg/dl, lactic dehydrogenase 310 IU/l, calcium 10.2 mg/dl, total proteins 7.2 gr/dl, albumin 4.3 gr/dl, and b2microglobulin 3,085 mg/l. The patient was treated by radiation therapy in order to diminish the size of the neoplastic mass and relief from symptoms. He underwent five sessions of low dose radiotherapy (20 Gy) and was then treated with chemotherapy with four cycles of VAD (liposomal doxorubicin) regimen. Four months after completing treatment the patient is free of symptoms and the swelling has disappeared (recent photograph not available). In fact, during the last follow-up visit he presented hemoglobin level of 14.6 gr/dl, white cell blood count 7.240/ml, platelets 138.000/ml, ESR 3 mm/h, CRP 2 mg/dl, creatinine 1.2 mg/dl, urea 54 mg/dl, lactic dehydrogenase 306 IU/l, calcium 10.5 mg/dl, total proteins 7.6 gr/dl, albumin 4.5 gr/dl, and b2-microglobulin 3,118 mg/l, and IgG: 10.6 gr/l, IgA: 1.46 gr/l, IgM: 0.3 gr/l, k: 2.49 gr/l, l: 1.41 gr/l, k/l: 1.77 in the quantification of the serum immunoglobulins.