FDG PET/CT versus CT, MR imaging, and 67Ga scintigraphy in the posttherapy evaluation of malignant lymphoma.

Malignant lymphoma is the most common form of hematologic cancer, yet because of advanced methods of assessment, the traditional histology-based classification of lymphoma is insufficient for understanding lymphoma imaging. Still, radiologists should be familiar with the imaging findings in lymphoma. Integrated positron emission tomography (PET)-computed tomography (CT) allows improved diagnostic accuracy, and uptake of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) can help predict response during treatment. The sensitivity and specificity of FDG PET are superior to those of gallium 67 scintigraphy in all but indolent lymphoma. Both magnetic resonance (MR) imaging and CT allow excellent assessment of bone texture, but FDG PET is superior in demonstrating bone marrow metabolic activity. Thus, FDG PET is important in both the primary diagnosis and the evaluation of therapy in lymphoma. It may be difficult to determine whether residual abnormalities seen after the completion of chemotherapy-radiation therapy represent residual tumor or fibrotic tissue, but PET/CT may allow more accurate diagnosis than MR imaging or CT, thereby helping identify patients who require more intensive treatment. Some diagnostic pitfalls are encountered at FDG PET. However, anatomic CT helps localize and define disease and avoid these potential pitfalls.

Severe degenerative change of multiple organs mediated by chronic active Epstein-Barr virus infection with infected T-cell expansion.

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs.

Thalidomide-induced severe neutropenia during treatment of multiple myeloma.

Recent reports have shown that thalidomide has antiangiogenic activity and is effective for the treatment of refractory multiple myeloma. Unlike other antineoplastic drugs, thalidomide is reported to rarely cause severe hematologic toxicity. In Keio University Hospital, 44 patients with refractory multiple myeloma, including 18 who had relapsed after hematopoietic stem cell transplantation, were treated with this drug as a single agent. Severe grade 3 or 4 neutropenia during thalidomide treatment was observed in 10 patients. This phenomenon was not noted in previous reports. Neutropenia usually occurred in the first or second week of treatment. Concomitant progression of thrombocytopenia occurred in 5 cases, and bone marrow hypoplasia without a significant increase in myeloma cell numbers was also observed in 5 cases. Neutropenia was not correlated with anti-tumor response or the plasma concentration of thalidomide but was more frequently observed in patients with a low neutrophil and platelet count, anemia, or a high plasma cell percentage in the bone marrow before thalidomide treatment. Thus, this drug should be used carefully for patients with pretreatment cytopenia or a high tumor burden in the bone marrow.

Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: a case report and review of the literature.

Myelodysplastic syndrome (MDS) often transforms into acute leukemia, usually of a myeloid phenotype. However, the transformation of MDS into acute lymphoblastic leukemia (ALL) is extremely rare. We present a case of refractory anemia with excess of blasts (RAEB) that transformed into ALL. MDS (RAEB) was diagnosed in a 68-year-old Japanese woman in August 2001. Two months later, MDS progressed to erythroleukemia (French-American-British [FAB]classification, acute myeloid leukemia [AML]-M6), and in December, 2001, she was treated with combined chemotherapy containing aclarubicin, cytarabine, and granulocyte colony-stimulating factor, which improved her clinical symptoms. However, 1 month after the chemotherapy, she developed ALL. The blasts at that time had a markedly basophilic cytoplasm with multiple cytoplasmic vacuoles, and their morphology mimicked that of ALL-L3. The blasts also expressed CD13, a myeloid marker, in addition to lymphoid markers. Southern-blot analysis revealed rearrangement of the immunoglobulin heavy chain, but no additional chromosomal abnormality characteristic of ALL-L3 was detected. The patient was treated with chemotherapy, but she developed tumor lysis syndrome and died of multiple organ failure. Although the precise mechanism of lymphoid transformation is not yet fully understood, this case clinically supports the nature of MDS as a pluripotent hematopoietic stem cell disorder.

[Improvement of diabetes insipidus after allogeneic bone marrow transplantation in a patient with myelodysplastic syndrome].

A 45-year-old male was diagnosed as having myelodysplastic syndrome (RAEB) in March 2001. He was admitted to our hospital because of cellulitis in his left lower limb in May. The blood cell count showed pancytopenia and immature myeloid cells were seen in the peripheral blood. Bone marrow aspiration showed the proliferation of myeloblasts (11.2%) and complex karyotypic abnormalities were detected including the long arm deletion of chromosome 7. The patient developed polyuria and polydipsia after admission and was diagnosed as having central diabetes insipidus. He was treated with DDAVP and the polyuria disappeared. In November, he underwent unrelated allogeneic bone marrow transplantation after conditioning with total body irradiation and cytarabine. After transplantation DDAVP was no longer required. Central diabetes insipidus has been reported as a rare complication of leukemia or myelodysplastic syndrome, but the underlying mechanism remains unclear. The complete remission of diabetes insipidus after bone marrow transplantation suggests that the infiltration of leukemic cells into the pituitary gland caused the diabetes insipidus in this case.

Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid.

A 32-year-old woman with relapsed Philadelphia chromosome-positive acute lymphoblastic leukaemia was treated with imatinib mesylate (formerly STI571), a selective inhibitor of BCR/ABL tyrosine kinase. Although the initial marrow response was good and stably maintained, she subsequently relapsed with extensive infiltration of leukaemic cells into the central nervous system (CNS). After controlling her CNS disease with additional intrathecal chemotherapy, we measured the concentration of imatinib in cerebrospinal fluid (CSF) and blood simultaneously. The concentration of imatinib in CSF was about 92-fold lower than that in blood. These results suggest that imatinib poorly penetrates the blood-brain barrier and has limited activity against CNS leukaemia.

Thalidomide for the treatment of refractory multiple myeloma: association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome.

Recent reports showed that thalidomide has anti-angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty-four evaluable patients (42%) showed more than 25% reduction of M-protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2 - 4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (2.0 microg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near-normal ranges in responders but were still high in most non-responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P = 0.025), but not in non-responders (P = 0.37). Reduction of plasma VEGF level might be an important indicator for anti-myeloma effect of thalidomide.

Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity.

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg ml vs. 1.58 pg/ml, P < 0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P < 0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with beta2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.