Eugenia Quartarone

Bisphosphonate-Associated Osteonecrosis of the Jaw in Patients with Multiple Myeloma and Breast Cancer

Osteonecrosis of the jaw is an unremitting adverse outcome associated with bisphosphonate therapy in patients with multiple myeloma or bone metastases from solid tumors. Twelve patients who presented with exposed bone associated with bisphosphonates were reviewed to determine the type, dosage and duration of their bisphosphonate therapy, presenting findings, comorbidities and the event that incited the bone exposure. The discontinuation of bisphosphonate therapy has not helped reverse the presence of osteonecrosis, and the surgical manipulation of the involved site appears to worsen the underlying bone pathology. Hyperbaric oxygen, which has proven efficacious in other forms of osteonecrosis by establishing an oxygen gradient, is of no definitive benefit to patients with bisphosphonate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swelling but ineffective in preventing the progression of the exposed bone. To date, prevention is the only currently possible therapeutic approach to the management of this complication.

Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies

The system involving angiopoietin‐2 (Ang‐2) and its receptor, Tie‐2, appears to play an important role not only in tumor angiogenesis, but also in the biology of haematological and non‐haematological malignancies. In the present study we evaluated the serum levels of soluble Ang‐2 (sAng‐2) and soluble Tie‐2 (sTie‐2) in patients with haematological malignancies. Measurements were carried out in 15 patients with chronic myeloid leukaemia (CML), 25 with essential thrombocythemia (ET), 24 with multiple myeloma (MM) and six with monoclonal gammopathy of undetermined significance (MGUS). In addition, we correlated the levels of angiopoietins with known prognostic factors. sAng‐2 and sTie‐2 were quantified with enzyme‐linked immunosorbent assay (ELISA). In patients with CML and MM the levels of sAng‐2 were significantly higher (1686.53 ± 936.41 pg/mL and 1917.82 ± 1427 pg/mL, respectively) than in controls (n = 15; 996.096 ± 414.65 pg/mL) (P < 0.01). In patients with MM sAng‐2 levels were significantly increased with increasing stage of disease, from stage I to stage III (P < 0.03) and presented a trend of correlation with Beta2‐microglobulin levels (r = 0.317) and grade of bone involvement. Furthermore, the levels of sAng‐2 determined after 6 months of chemotherapy in CML patients were significantly lower than at diagnosis in the patients who achieved haematological remission. Circulating sTie‐2 levels were increased in patients with ET (17.5 ± 9.2 vs 9 ± 3.5 ng/mL; P < 0.01) and in those with CML (16.29 ± 8.7 ng/mL; P < 0.04). In conclusion, abnormal levels of sAng‐2 and sTie‐2 are present in some haematological malignancies. These markers may play a role in the pathophysiology of these conditions and their progression.

Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases

Authors evaluated some markers of angiogenetic activity in patients with chronic myeloproliferative diseases (CMDs). In this study by using a cytofluorimetric analysis we evaluated circulating endothelial progenitor cells (EPCs) in patients with chronic myeloproliferative disease. Moreover, in the same group of subjects, we evaluated serum levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor‐2 (VEGFR2). In our patients, we have found an increase in the number of endothelial progenitor cells in primary myelofibrosis (PMF) and polycythaemia vera (PV) patients, while an increase of circulating endothelial cells (CECs) was found in all patients with CMD. Moreover, we found higher serum levels of VEGF with respect to control subjects in every group of patients with CMD, and a not significant reduction of VEGFR2 levels in essential thrombocythaemia (ET) patients. A correlation was also found in PV patients between VEGF levels and erythrocyte number and in PMF subjects with the count of white cells. Our data suggest that some markers of angiogenesis are activated in CMD patients and angiogenesis may have a role in the pathophysiology of chronic myeloproliferative disorders. Copyright

Patients with bisphosphonate-associated osteonecrosis of the jaw have unmodified levels of soluble vascular endothelial growth factor receptor 1.

In an article recently published in Leukemia and Lymphoma, Pozzi et al. reported 35 cases of bisphosphonate-associated osteonecrosis of the jaw (ONJ) in multiple myeloma patients [1]. In fact, sinc...

Serum levels of interleukin-16 in lymphoid malignancies

Interleukin-16 (IL-16), also named lymphocytic chemoattractant factor, is produced mainly by CD8þ peripheral blood lymphocytes but also by CD4þ T cells, eosinophils, mast cells, and bronchial epithelial cells after stimulation. IL-16 induces chemotaxis of CD4þ T cells, monocytes, and eosinophils [1]. The cytokine contributes in fact to the regulatory process of CD4þ cell recruitment and activation at sites of inflammation [2]. In addition, it stimulates the production of cytokines such as IL-6, TNF-alpha, IL-1, and IL-15 by monocytes, playing an essential role in initiating the inflammatory response [3]. It was recently reported that B-lymphocytes too express IL-16 mRNA and synthetize protein [4], and that the levels of IL-16 can be modified in lymphoid neoplastic diseases. Previous studies reported that serum IL-16 levels were higher in untreated multiple myeloma (MM) patients as compared with normal controls and that there was a strong correlation between the serum IL-16 level and disease activity [5]. Moreover, it has recently been reported that IL16 mRNA was detected in all of 18 mycosis fungoides (MF) lesions investigated by an in situ hybridization technique, suggesting that IL-16 might be involved in skin homing in MF [6]. In our study, we investigated the levels of IL-16 in sera of patients affected by haematologic malignancies and correlated them with known prognostic factors to provide preliminary insights on the biological relevance of this cytokine in selected haematologic malignancies. Sixty-four previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/ SLL) patients were included in this study. Their median age was 65 years (range 43 – 87) and the male/female ratio was 35:29. Routine laboratory studies consisted of complete blood count with differential, platelet count, and blood chemistry including beta-2microglobulin (b2m) and lactate dehydrogenase (LDH), as well as immunonophenotyping. Physical examination, chest X-ray, and abdominal ultrasound were performed in all instances. In this group of patients a bone marrow biopsy allowed us to select 52 patients with B-chronic lymphocytic leukemia (B-CLL) that were clinically staged according to the Rai system and distributed as follows: Stage 0, 14; Stages I – II, 28; and Stages III – IV, 10. Four previously untreated patients with mantle cell lymphoma and five with follicular lymphoma were also studied. Their median age was 64 years (range 47 – 79). Diagnosis was made by routine histological and immunohistochemical examination. The study population included 19 newly diagnosed patients with MM with a median age of 62 years (range 37 – 78 years). According to the DurieSalmon staging system, three patients had MM disease stage I, nine patients had stage II, and seven patients had disease stage III. The paraprotein class was immunoglobulin IgG in 12 patients and IgA in 7 patients. Serum samples were collected from patients and from 20 ageand sex-matched normal controls and were aliquoted into separate vials and stored at 7708C until use. Informed consent was obtained from all individuals participating in the study. The

Wernicke's encephalopathy after allogeneic stem cell transplantation.

Wernickes encephalopathy is an acute neuropsychiatric condition due to thiamine deficiency frequently associated with chronic alcohol abuse. We describe 2 cases of patients who experienced acute Wernickes encephalopathy after allogeneic stem cell transplantation associated with the use of commercial total parental nutrition. Early diagnosis with magnetic resonance imaging and timely treatment with thiamine resulted in rapid resolution of clinical and radiological signs. In conclusion, the prolonged use of commercial total parental nutrition formulas must be supplemented with thiamine in the form of intramuscularly administered multivitamins.

Imatinib mesylate treatment in a patient with chemoresistant Ph+ acute myeloid leukemia: possible role of Wilms' tumor gene 1.

than 8 months 1 . Imatinib mesylate, an effective and selective inhibitor of BCR-ABL tyrosine kinase activity, is commonly used in the treatment of Ph-positive chronic myeloid leukemia (CML), also in the blastic phase, whereas its role in the treatment of Ph+ AML is not yet well understood. To our knowledge, few cases of Ph + AML have been treated with imatinib mesylate 2,3 .

Fludarabine based treatment caused improvement of anemia in a patient with T-cell LGL leukemia despite evidence of the persistence of the abnormal T-cell clone

Clonal diseases of large granular lymphocytes (LGLs) are rare lymphoproliferative malignancies that arise from either mature T-cell (CD3þ) or natural killer (NK)-cell (CD3) lineages. There are four distinct diseases involving LGLs: T-cell LGL leukemia, aggressive T-cell LGL leukemia, chronic NK-cell leukemia and aggressive NK-cell leukemia [1]. These disorders are often found in older people, with an average age at initial examination of *60 years [2]. Although most cases of LGL leukemia behave in an indolent manner, *60% of patients become symptomatic during the course of their disease [3,4]. Systemic symptoms, neutropenia, lymphocytosis, anemia are in fact frequent. Anemia caused by various pathogenic mechanisms such as Coombs’ positive autoimmune hemolysis, pure red aplasia, decreased erythroid marrow progenitors, was reported in 48% of patients, and erythropoietin has been employed as first-line therapy with beneficial effects for the treatment of anemia due to LGL leukemia [5]. Here we report a 72-year-old woman with a T-cell LGL leukemia presenting with a severe and progressive anemia. Treatment with fludarabine (FA) resulted in a clinical response and improvement of anemia despite evidence of the persistence of the abnormal T-cell clone. In August 2006, a 72-year-old woman presented to our division with a diagnosis of anemia and lymphocytosis. She presented a red blood cell count of 2.756 10/L, hemoglobin of 8.4 g/dL, and hematocrit of 25.6. She had no subjective symptoms but asthenia, and her physical examination did not reveal lymphadenopathy, hepatomegaly whereas she had moderate splenomegaly. In the last 3 months her anemia had progressed from 10.5 g/dL. She had a white blood count (WBC) of 8.86 10 /L with 94% lymphocytes and a platelet count of 2386 10/L. The peripheral blood lymphocytes had round nuclei and azurophilic granules in May–Giemsa-stained films. Serum lactate dehydrogenase was 475 IU/L. Flow cytometry of the peripheral blood cells demonstrated that 96% were CD3þ, 87% CD2þ, 11% CD4þ, 11% CD8þ, 14% CD5þ, 16% CD7þ, 6% CD56þ, 75% CD111c. A bone marrow biopsy demonstrated infiltration of 60% lymphocytes. A rearranged band in the TCR chain gene was detected. The patient was diagnosed as having T-cell LGL leukemia. After discharge in September 2006, the number of RBCs and concentration of Hb worsened gradually over about 1 year although she was in treatment with erythropoietin or she had a transfusion support. In July 2007, she had a WBC level of 8.86 10/L, with 80% lymphocytes, RBC of 2.156 10/L, Hb of