Non-Hodgkin's lymphoma presenting as multiple bone lesions and hypercalcemia.

We report a rare case of a patient with non-Hodgkin's lymphoma who developed multiple bone lesions and hypercalcemia. A 50-year-old woman complained of drowsiness and multiple bone pain on admission. Radiographic examination revealed multiple bone fractures and osteolytic lesions. She was diagnosed with diffuse large B cell lymphoma by biopsy of an inguinal lymph node. Elevation of parathyroid hormone-related protein (PTHrP) and hypercalcemia were confirmed pretreatment, and those serum levels decreased during chemotherapy for lymphoma. However, the disease was resistant to chemotherapy combined with rituximab. These findings suggest that hypercalcemia is associated with PTHrP and the prognosis of patients with bone lymphoma in advanced stage is poor, although it is thought to be a relatively favorable prognosis in localized primary lymphoma of bone.

Idiopathic thrombocytopenic purpura and myasthenia gravis after fludarabine treatment for chronic lymphocytic leukemia.

We report a patient with chronic lymphocytic leukemia (CLL) who developed idiopathic thrombocytopenic purpura (ITP) and myasthenia gravis (MG) after fludarabine therapy. ITP developed after 6 cycles of fludarabine treatment, and MG occurred 2 months after the onset of ITP. MG was successfully treated with immunosuppressive therapy and plasma exchange, while rituximab was effective for CLL and ITP. Fludarabine seemed to have an important role in the onset of ITP and MG in this case.

[Outcome of allogeneic stem cell transplantation for hematological disorders in patients older than 50].

We retrospectively evaluated the outcomes in patients older than 50 years of age who underwent allogeneic hematopoietic transplantation. Twenty-three patients received conventional stem cell transplantation (CST) and 9 patients received reduced intensity stem cell transplantation (RIST). Regimen-related toxicity was observed in 21 (91%) patients with CST and 4 (44%) patients with RIST. Early death occurred within 100 days after transplantation in 6 patients with CST and 2 patients with RIST. Among the patients with complete remission, the two-year probability rate of survival was 44% in patients with CST and 100% in patients with RIST (p=0.08). Among the patients without complete remission, the two-year probability rate of survival was 30% in patients with CST and 0% in those with RIST (p=0.08). For patients receiving RIST without complete remission, relapse and infection were the main causes of death. Our data suggest that patients without complete remission should receive CST to the degree possible.

A possible association between the presence of interleukin-4-secreting cells and a reduction in the risk of acute graft-versus-host disease.

OBJECTIVE: We monitored cytokine-secreting cells using an enzyme-linked immunospot (ELISPOT) assay in a prospective study to assess the cytokine network after transplantation. PATIENTS AND METHODS: Peripheral blood mononuclear cells were collected from 23 patients who received allogeneic stem cell transplantation, from before the preconditioning regimen to 56 days after transplantation. The number of interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha)-secreting cells were measured by ELISPOT assay. For IL-4 and IFN-gamma, in vitro stimulation with phorbol 12-myristate 13-acetate and phytohemagglutinin was performed. RESULTS: The frequency of IL-4-secreting cells was significantly higher in five patients receiving peripheral blood stem cell transplantation (PBSCT) than that in 18 patients who received bone marrow transplantation (BMT). Based on IFN-gamma and TNF-alpha release, there was a trend toward a decrease in the number of cytokine-secreting cells in PBSCT compared with BMT. Furthermore, patients who did not develop acute graft-vs-host disease (GVHD, n=5) showed a significantly higher number of IL-4-secreting cells compared with those who developed acute GVHD (n=18). Both IFN-gamma-secreting cells and TNF-alpha-secreting cells showed a trend to increase in number in patients with acute GVHD. In patients who received reduced-intensity stem cell transplantation (n=7) compared with conventional stem cell transplantation (n=16), there was a large number of cytokine-secreting cells detected by IL-4 and IFN-gamma release. CONCLUSIONS: These results are consistent with the hypothesis that IL-4-producing cells inhibit the development of acute GVHD. In addition, the increased percentage of IL-4-secreting cells may be responsible for the unexpected low incidence of acute GVHD in PBSCT, despite the presence of large numbers of mature T cells in the donor infusion.

[Pulmonary MALT lymphoma with macroglobulinemia].

An 84-year-old man was diagnosed as having pulmonary MALT lymphoma in January 1997. Six years later, he was admitted to our hospital with coughing and dyspnea in November 2003. Dissemination of MALT lymphoma was confirmed by findings of pleural effusion and bone marrow aspiration. A FISH analysis of cells from the pleural effusion revealed t(11;18)(q21;q21) and the serum level of IgM was 8,600 mg/dl (M-protein). The diagnosis of secondary macroglobulinemia was made. The patient received rituximab monotherapy because he was very elderly. Pleural effusion has not been seen after the administration of rituximab, although there have been no changes in the lung mass and serum values of M-protein.

[Triple secondary malignancy of gingiva, palate and esophagus after an allogeneic bone marrow transplantation for cutaneous T-cell lymphoma].

A 31-year-old man was diagnosed as having cutaneous T-cell lymphoma in January 1994. He received an allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor in May 1995, because of refractoriness to chemotherapy. The patient had been treated with immunosuppressants including prednisolone and cyclosporin A for chronic graft-versus-host disease (GVHD) of the extensive type following acute GVHD. Five years after the BMT, he developed moderately differentiated squamous cell carcinoma (SCC) on the mandibular gingival mucosa and underwent surgical resection. Furthermore, 6 years after the BMT well differentiated SCC developed on his palate and was resected. Concurrently, he was diagnosed as having esophageal cancer (poorly differentiated SCC) and underwent a subtotal esophagotomy. One year later he had a recurrence of the esophageal cancer with dysphagia and was treated with radiation and chemotherapy. He remains free of triple cancer and lymphoma. It is suggested that total body irradiation, immunosuppressants, and chronic GVHD are associated with a risk of secondary malignancies following allogeneic BMT. These factors might have contributed to the onset of triple cancer in our patient.

Long-term cytogenetic remission with ubenimex monotherapy in a case of chronic myeloid leukemia.

A 65-year-old man was diagnosed with chronic myeloid leukemia (CML) in February 1990, and was treated with busulfan and ubenimex. Cytogenetic analysis of the bone marrow revealed the Philadelphia (Ph) chromosome in 100% of cells of analyzed at diagnosis. Treatment with busulfan was stopped in March 1993 due to bone marrow suppression. The Ph chromosome was seen in 80% of cells in June 1993. He received ubenimex monotherapy after cessation of busulfan. Complete disappearance of the Ph chromosome was confirmed in May 1995 and has continued to date. This suggests that ubenimex might specifically affect the Ph chromosome and be useful as maintenance therapy for CML.

Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.

The linking of integrin to cytoskeleton is a critical event for an effective cell migration. Previously, we have reported that a novel integrin-linked kinase (ILK)-binding protein, affixin, is closely involved in the linkage between integrin and cytoskeleton in combination with ILK. In the present work, we demonstrated that the second calponin homology domain of affixin directly interacts with alpha-actinin in an ILK kinase activity-dependent manner, suggesting that integrin-ILK signaling evoked by substrate adhesion induces affixin-alpha-actinin interaction. The overexpression of a peptide corresponding to the alpha-actinin-binding site of affixin as well as the knockdown of endogenous affixin by small interference RNA resulted in the blockade of cell spreading. Time-lapse observation revealed that in both experiments cells were round with small peripheral blebs and failed to develop lamellipodia, suggesting that the ILK-affixin complex serves as an integrin-anchoring site for alpha-actinin and thereby mediates integrin signaling to alpha-actinin, which has been shown to play a critical role in actin polymerization at focal adhesions.

Clinical features and outcome in HCV-positive aggressive non-Hodgkin's lymphoma.

The clinical features and outcome of 25 previously untreated aggressive non-Hodgidn's lymphoma (NHL) patients with hepatitis C virus (HCV) infection were evaluated retrospectively. The patients included 18 males and 7 females with a median age of 66 years. The median observation period for survivors was 32 months. Although there were no patients with hepatocellular carcinoma during the follow-up period, 7 patients had cirrhosis (LC) at the initiation of therapy for NHL. Seventeen patients (68%) had initial extranodal involvement including 2 cases with liver involvement. The 5-year overall survival (OS) rate in the whole group was 46%, and the 5-year relapse-free survival (RFS) rate of patients with complete response (CR) was 48%. Patients with non-cirrhosis (n = 18) showed better OS (P = 0.04) compared with patients with LC (n = 7) and 5-year OS rates were 55 and 21%, respectively. Fourteen patients died in the whole group; 4 of NHL and 2 of liver failure in the LC group and 8 of NHL in the non-cirrhotic group. Among the latter 8 patients, cumulative dose (CD) of doxorubicin (ADR) and cyclophosphamide (CPA) were significantly lower than those of survivors with non-cirrhosis. In conclusion, patients with HCV-positive aggressive NHL have a similar prognosis as HCV-negative aggressive NHL. In non-cirrhotic patients, attention should be paid to the CD of drugs required to cure the aggressive NHL.

Involvement of central nervous system in prolymphocytoid transformation of chronic lymphocytic leukemia.

We report a rare case of involvement of the central nervous system (CNS) by chronic lymphocytic leukemia (CLL). A 68-year-old man with prolymphocytic variant of B-CLL (CLL/PLL), develops CNS involvement with headache and vomiting. Computed tomography of the head showed no abnormalities. The cerebrospinal fluid (CSF) revealed numerous lymphocytoid cells of prolymphocytic appearance consistent with findings on the peripheral blood smear. Immunophenotypic analysis demonstrated that the leukemic B cells were positive for CD19, CD20, and HLA-DR, but CD5 was difficult to detect. The patient was treated with intrathecal methotrexate, cytarabine, and hydrocortisone and had improvement in symptoms and CSF findings. Although CNS involvement is an unusual manifestation in CLL, one should be aware of the possibility of this complication in cases presenting with neurological symptoms.

Merkel cell carcinoma developing after antithymocyte globulin and cyclosporine therapy for aplastic anemia.

We report a patient who developed Merkel cell carcinoma (MCC) after treatment with antithymocyte globulin and cyclosporine for aplastic anemia. The clinical course was progressive and poor prognosis. Although MCC is relatively rare in second cancers arising after immunosuppressive therapy, patients should be closely monitored for the development of this complication as well as other second malignancies.

Clinical significance of fragmented red cells after allogeneic bone marrow transplantation.

To clarify the clinical significance of the presence of fragmented red cells (FRC) after allogeneic bone marrow transplantation (BMT), we measured the incidence and degree of FRC and their relationships to clinical features. The percentages of FRC (%FRC) were measured in 50 patients on weeks -2, 0, 2, 4, 6, 8, 10, and 12. The %FRC in pre-BMT patients (mean, 0.52%; range, 0.04%-1.56%) was higher than in healthy control subjects (mean, 0.08%; range, 0.02%-0.27%). The highest %FRC (> or = 1.3%) were seen in 2 pre-BMT and 17 post-BMT patients. Eight patients who developed thrombotic microangiopathy (TMA) showed %FRC values that were significantly higher than those in patients without TMA. However, the timing of elevated %FRC was delayed until several days after the onset of intravascular hemolysis and/or a drop in platelet count. Of the patients who did not experience TMA, 5 patients with infection and 4 patients with acute graft-versus-host disease (GVHD) also showed significant elevation of %FRC during the clinical course. Furthermore, multivariate analysis results demonstrated that TMA and infection had a statistically significant effect on the high value of %FRC. These findings indicate that the appearance of FRC is a common phenomenon in patients undergoing BMT and is not a predictive factor for the early diagnosis of TMA, although FRC is one of the main laboratory findings in TMA. Furthermore, an increased %FRC is seen in other post-BMT clinical settings, such as infection and acute GVHD.

Possible role of ILK-affixin complex in integrin-cytoskeleton linkage during platelet aggregation.

Integrin-mediated adhesion induces the formation of focal adhesions that link the extracellular matrix and intracellular actin cytoskeletal networks. We previously showed that integrin-linked kinase (ILK), which can interact with beta1 and beta3 integrins, and its interacting protein, affixin, play an essential role in the initial assembly of focal adhesion structures and actin stress fibers. Although the relevant structures are also observed in integrin alphaIIbbeta3 in platelets, the precise underlying molecular mechanism remains unclarified. Here, we found that ILK stably forms a complex with ss-affixin in platelets. Thrombin stimulation induces their association with integrin beta3, which is followed by their incorporation into the Triton-insoluble membrane-cytoskeletal fraction. During the course of thrombin-induced platelet aggregation, ILK activity was enhanced within 90s to 2.1-fold of the basal level, independent of phosphatidylinositol 3-kinase. Taken together with the observation that the treatment with an anti-integrin beta3 antibody stimulates ILK activity without inducing platelet aggregation, these results suggest that the outside-in signaling induced by fibrinogen binding to integrin enhances ILK activity and results in the initial phase to reorganize the actin cytoskeleton.