Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome.

Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated. Seventy-three months after the diagnosis, a bone marrow examination revealed increased myeloblasts, at which time computed tomography showed diffuse ground-glass opacities and interlobular septal thickening in the bilateral lower lung fields. A lung biopsy revealed the presence of PAP; therefore, the clinical diagnosis of MDS/sPAP was confirmed. Careful attention should be paid to the development of sPAP in MDS patients with pulmonary lesions during azacitidine treatment.

Persistent clonal cytogenetic abnormality with del(20q) from an initial diagnosis of acute promyelocytic leukemia.

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia.

The incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type 1 carriers in Japan.

Human T-lymphotropic virus type 1 (HTLV-1) is highly endemic in the Kyushu/Okinawa region of Japan. A nationwide investigation verified the frequency of HTLV-1 carriers among first-time blood donors and the occurrence of newly diagnosed adult T-cell leukemia/lymphoma (ATL) cases from 2007 through 2008. After adjusting for differences in capture rate between areas, the age-, sex- and area-specific incidence of ATL among carriers was determined. Annual ATL incidence among 10 000 carriers was 7.7 and 8.7 for the Kyushu and non-Kyushu/Okinawa regions, respectively. The incidence increased sharply for men from their 40s to their 70s, but the rate in females remained unchanged through their 40s to 70s. ATL incidence in middle-aged females was still low, even if female carrier frequency was assumed to be identical to that of males. Patients with ATL in their 60s and 70s will comprise two-thirds of all patients with ATL for the next 15 years in Japan.

Nationwide survey of adult T-cell leukemia/lymphoma (ATL) in Japan.

In a nationwide survey of ATL in Japan, a total of 910 cases of ATL and 7,164 cases of B-NHL as a control disease, newly diagnosed from January 2006 to December 2007 (2 years), were enrolled from 156 hospitals. Male-female ratios were 1.16 for ATL and 1.22 for B-NHL. Among all ATL cases registered, 59.8% were from an HTLV-1 endemic area in Kyushu, and the ratio of ATL to B-NHL in this area was 1 to 3, while that in a non-endemic area in Tokyo was 1 to 40. Compared to previous nationwide studies, the age of ATL patients shifted toward older ages and the mean age gradually increased from 52.7 years in the first survey (cases before 1980) to 61.1 years in the ninth survey (1996-1997) and, finally, to 66.0 years in the present study (range: 19 to 94, median: 67). On subtype classification, 46.7% were classified as the acute type, 34.8% the lymphoma type, 10.3% the smoldering type, and 8.2% the chronic type, and the rate of the acute type decreased with an increase in the lymphoma type compared to that in previous studies. An increase in the mean age is explained by the high HTLV-1 prevalence in elderly people over 64 years old in endemic areas (20%), and by the continual development of ATL from this large pool of HTLV-1 carriers. According to mortality statistics from the Ministry of Health, Labor and Welfare in Japan, approximately 1,000 people die annually from ATL, a statistic that has not changed at least for the past decade.

Aberrant overexpression of membrane-associated mucin contributes to tumor progression in adult T-cell leukemia/lymphoma cells.

Aberrant overexpression of membrane-associated mucin (MUC1) is implicated in the pathogenesis of cancer, particularly of adenocarcinomas. Adult T-cell leukemia/lymphoma (ATL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), exhibits invasive tropism into various organs, resulting in disease progression and resistance to treatment. In the present study, we showed that MUC1 is overexpressed exclusively in cells of ATL among hematological malignancies. Furthermore, increased expression of MUC1 correlated with a poor prognosis, suggesting MUC1 to be a prognostic marker in ATL. Various functional analyses with knockdown experiments using a specific siRNA for MUC1 revealed that MUC1 is involved in cell growth, cell aggregation, and resistance to apoptosis. Although it has been shown that the anti-adhesive properties of MUC1 facilitate migration and metastasis of tumor cells, our findings indicated that MUC1 contributes to cell-cell adhesion. Mucins thus seem to play a role in the pathogenesis and/or progression of ATL.

Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group.

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.

High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma.

We surveyed IL-21 receptor (IL-21R) in leukemia and lymphoma and found that follicular lymphoma cells showed exceptionally high IL-21R expression. Notably, IL-21 showed divergent effects depending on the cell origin: growth stimulation in Burkitt lymphoma cell lines and adult T cell leukemia/lymphoma cell lines but induction of apoptosis in B lymphoma cell lines with t(14;18)(q32;q21), a marker karyotype of follicular lymphoma. IL-21 activated caspase-8 and -3 and reduced mitochondrial membrane potential. More importantly, IL-21 decreased Bcl-2 expression but increased Bax expression. These results support a new therapeutic approach using the IL-21/IL-21R system in follicular lymphoma.

Imatinib provides durable molecular and cytogenetic responses in a practical setting for both newly diagnosed and previously treated chronic myelogenous leukemia: a study in nagasaki prefecture, Japan.

To evaluate the efficacy of imatinib in a practical setting, we registered 43 patients with newly diagnosed chronic myelogenous leukemia (CML) (group I) and 56 patients with previously diagnosed CML (group II) at 11 hematology centers in Nagasaki prefecture, Japan, from December 2001 to July 2005 and analyzed the molecular responses. Cytopenia, fluid retention, and skin rash were major adverse events, along with elevation in creatine phosphokinase levels. With a follow-up of approximately 3.5 years, imatinib treatment led to 88.7% overall survival (OS) and 85.2% progression-free survival (PFS) rates for group I, and 79.8% OS and 76.6% PFS rates for group II; the rates were not significantly different despite a lower average imatinib dose in group II. The rates of complete cytogenetic response at 30 months and major molecular response at 24 months were 86.1% and 62.5%, respectively, in group I, and 77.9% and 58.3% in group II; the rates were not significantly different. As has been reported by other groups, these results demonstrate that imatinib treatment can provide excellent clinical and molecular effects for not only newly diagnosed but also previously treated CML patients in practical settings that cover a wider variety of patients than clinical trials.

Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T-cell origin with multi-organ involvement. Because the chemokine receptors play crucial roles in tissue-specific homing of mature lymphocytes, particular chemokine receptors expressed on ATLL cells may be involved in their tissue infiltration. We thus performed a comprehensive survey on the chemokine receptor expression in ATLL. ATLL cells expressed transcripts of CCR1, CCR4, CCR7, CCR8, CCR10 and CXCR4 but hardly expressed those of CCR2, CCR3, CCR5, CCR6, CCR9, CXCR1, CXCR2, CXCR3 and CXCR5. These results were confirmed at the protein level by flow cytometric analysis. Notably, patients who have skin lesions showed significantly higher levels of CCR10 mRNA expression than patients without skin lesions. ATLL cells migrated efficiently to the CCR4 ligand, CCL22, and moderately to the CCR10 ligands, CCL27 and CCL28. Moreover, ATLL skin lesions consistently contained transcripts of CCR10 and its ligands CCL27 and CCL28 besides those of CCR4 and its ligands CCL17 and CCL22 that have been reported previously. Collectively, the frequent co-expression of CCR4 and CCR10, the known pair of skin-homing chemokine receptors, may play an important role in ATLL invasion into the skin.

Prosthetic valve endocarditis due to Candida albicans treated successfully with medical treatment alone.

Prosthetic valve endocarditis (PVE) caused by Candida species is associated with high morbidity and mortality. A combination of surgical resection and antifungal drug therapy is the golden standard for treatment, yet surgical intervention is not possible in all cases of Candida PVE. We report a case of PVE due to Candida albicans cured by medical treatment alone. This case suggests that, in some instances, Candida PVE can be managed medically with antifungal therapy. Such a conservative approach should be applied with caution and necessitates very close follow-up on a long-term basis.