Abrupt evolution of Philadelphia chromosome-positive acute myeloid leukemia in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph-positive AML, which evolved during the course of low-risk MDS. The patient, a 76-year-old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph-positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph-positive AML in the course of low-risk MDS has rarely been reported. We report this case as a rare clinical course of MDS.

Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group.

AIMS: To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). CONCLUSIONS: Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients.

[Waldenström macroglobulinemia complicated with chylothorax].

An 81-year-old male had been diagnosed with Waldenström macroglobulinemia (WM) eight years previously and had thus been administered appropriate treatment. Left chylothorax later developed at 3 years and 8 months after the initial diagnosis. He was hospitalized with severe anemia, general fatigue, and appetite loss one year prior to this presentation and died due to a severe fungal infection. Autopsy revealed the presence of 1,300 ml chylothorax and infiltration of lymphoplasmacytic lymphoma (LPL) cells throughout his entire body. LPL cells were found to have invaded the excitation conducting system in the heart. In an evaluation of a resected lung tissue specimen of pneumothorax, subpleural infiltrated lymphoid cells were observed to show immunohistochemical positivity for IgM and bcl-2. Although these lymphoid cells were initially considered to be non-neoplastic lymphocytes, they were later determined to be LPL cells, which thus induced dilatation and proliferation of the lymph vessels. Chylothorax complications in patients with WM are rare events and only six such cases have so far been reported. The present case is considered to be an instructive one in which autopsy suggested the invasion of LPL cells to be involved in the development of arrhythmia, pneumothorax, and chylothorax before death.

[Loeys-Dietz syndrome with acute myeloid leukemia].

A 54-year-old man, who had been diagnosed with Loeys-Dietz syndrome based on his past history, family history, clinical findings, and the presence of a gene mutation, was referred to our hospital because of easy fatigability. Anemia, thrombocytopenia, and blasts in his peripheral blood were noted, and 31.4% blasts were found in a bone marrow aspiration. The blasts were positive for myeloperoxidase and esterase staining. Furthermore, karyotype analysis of bone marrow cells showed t(11;19)(q23;p13.1) and MLL abnormality was detected on RT-PCR A diagnosis of acute myeloid leukemia (M4) with 11q23 (MLL) abnormality was made. Loeys-Dietz syndrome is a Marfan-like congenital connective tissue disorder caused by a heterozygous missense mutation of a TGF-beta receptor I or II gene. The TGF-beta family inhibits the proliferation of normal epithelial cells and induces apoptosis, and is therefore known as a tumor suppressor factor. In this article, we discussed the association between Loeys-Dietz syndrome with a TGF-beta receptor gene mutation and cancer.

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

[Successful treatment of splenic lymphoma with villous lymphocytes by rituximab and laparoscopic splenectomy].

We report on a case of splenic lymphoma with villous lymphocytes (SLVL) which responded well to rituximab. A 50-year-old man was admitted because of splenomegaly. Abnormal lymphocytes of B cell lineage with moderately basophilic cytoplasm and unevenly distributed villi (villous cells) were found, both in the peripheral blood and bone marrow. CHOP and CHOP-E were performed, without any remarkable change in the size of the spleen. However, after infusion of rituximab (375 mg/m2, once weekly for 2 weeks), there was a marked reduction of the spleen size and the number of circulating villous cells. Splenectomy was performed afterwards, followed by 2 cycles of rituximab infusion. The patient is now followed on an outpatient basis without any sign of relapse.

Successful treatment with rituximab for angioimmunoblastic T-cell lymphoma.

We experienced a patient with angioimmunoblastic T-cell lymphoma (AITL) without Epstein-Barr virus-positive B (EBV-B) cells at initial presentation who progressed to AITL with expansion of EBV-B cells at relapse. Based on the results of repeated biopsy, the patient was successfully treated with rituximab in combination with chemotherapy at relapse. A repeat biopsy may be necessary to determine the optimum therapeutic strategy at relapse, particularly for patients with suspected expansion of B cell and/or EBV-B cells. Although a recent report found no significant prognostic advantage of rituximab, it is one of the active drugs for selected patients with AITL.

A Japanese family of typical Loeys-Dietz syndrome with a TGFBR2 mutation.

This report describes a Japanese family with vessel and craniofacial abnormalities. Although the clinical findings of the patient's father fulfilled the diagnostic criteria for Marfan syndrome, arterial tortuosity, aneurysms, hypertelorism and a bifid uvula were noted in both the patient and his father. These findings were compatible with the clinical manifestations that were previously reported in Loeys-Dietz syndrome. A molecular genetic analysis demonstrated a heterozygous missense mutation of the transforming growth factor-beta receptor II gene in both the patient and his father, which thus caused Loeys-Dietz syndrome. This is the first Japanese family case report of typical Loeys-Dietz syndrome.