Yoshihito Uchino

Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy.

Abstract The clinical significance of concurrent expression of MYC and BCL2 protein, known as “double-expressor lymphoma” (DEL), among patients with relapsed or refractory aggressive B-cell lymphomas, remains unclear. A retrospective analysis was performed of 38 patients treated with a salvage treatment consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone followed by consolidative high-dose chemotherapies. A total of 17 cases (45%) were categorized as DEL using immunohistochemical assay with a cut-off value of positivity of 40% for MYC and 50% for BCL2, respectively. DEL was associated with a lower overall response rate (35% vs 71%, p = 0.0481), worse 2-year progression-free survival (9% vs 67%, p = 0.001) and overall survival (35% vs 71%, p = 0.037). This analysis suggests that DEL is common among patients with relapsed/refractory aggressive B-cell lymphomas and that such patients require novel treatment strategies.

Safety and efficacy of high-dose cyclophosphamide, etoposide and ranimustine regimen followed by autologous peripheral blood stem cell transplant for patients with diffuse large B-cell lymphoma.

Abstract We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1–159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0–82.1) and 57.0% (95% CI, 39.5–71.2), respectively. Chronic renal impairment, therapy-related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed.

Negative impact of concurrent overexpression of MYC and BCL2 in patients with advanced diffuse large B-cell lymphoma treated with dose-intensified immunochemotherapy.

Abstract Co-expression of MYC and BCL2 proteins in diffuse large B-cell lymphoma (DLBCL), or ‘double-expressor lymphoma’ (DEL), results in poor patient prognosis, but the significance of DEL when aggressive treatments are applied remains uncertain. We performed a retrospective analysis of 40 patients with de novo DLBCL, who were categorized as being at high/high-intermediate risk according to the age-adjusted International Prognostic Index. Patients underwent an R-Double-CHOP regimen, a dose-intensified immunochemotherapy with or without consolidative high-dose chemotherapy followed by autologous stem cell transplantation. According to immunohistochemical analysis, 10 (25%) patients were categorized as having DEL, showing positivity for MYC (≥40%) and BCL2 (≥50%). The 3 year progression-free survival and overall survival of the DEL group were significantly worse compared with those of the non-DEL group (30% vs. 63%, p = 0.019 and 40% vs. 82%, p = 0.006, respectively). These results suggest that advanced DEL may need discrete treatment strategies.

Successful treatment of secondary Helicobacter pylori eradication for chronic immune thrombocytopenic purpura

Eradication of Helicobacter pylori (H. pylori) is one of the useful treatments of H. pylori-positive chronic immune thrombocytopenic purpura (ITP) [1, 2], and considered as a first-line treatment in Japan [3]. However, there are few reports concerning the efficacy of secondary eradication of residual H. pylori for chronic ITP. Here, we report a case of successful secondary eradication of residual H. pylori for chronic ITP. A 78-year-old man was referred to our hospital because of progressive thrombocytopenia. Initial investigations revealed normal hemoglobin (13.0 g/dl) and leukocyte count (3.5 10/l) and differentiation, but decreased platelet count to 51 10/l. Based on the clinical manifestation, laboratory tests and findings of bone marrow aspiration and biopsy, the patient was diagnosed as having chronic ITP. Because H. pylori infection was present by detecting anti-H.pylori IgG antibody, H. pylori eradication was selected as an initial treatment for ITP with amoxicillin, clarithromycin and proton pomp inhibitor (PPI). The patient had no gastrointestinal manifestation that associated with H. pylori infection or eradication. Two weeks after eradication, the platelet count increased to 88 10/l. However, H. pylori remained positive by the urea breath test. Six months after the first eradication, ITP was exacerbated with the decreased platelet count to 10 10/l, and the patient suffered from macroscopic hematuria. Although immunosuppressive therapy with prednisolone was recommended for the patient as a next therapeutic option, the patient declined any treatment other than secondary eradication of H. pylori. Therefore, after obtaining informed consent from the patient, we decided to treat the patient of secondary eradication with amoxicillin, metronidazole and PPI [4]. No serious adverse effect of this treatment was observed. Three months after the secondary eradication, the platelet count increased to 125 10/l without bleeding, and H. pylori had returned negative by the urea breath test. The platelet count remained normal 6 months after the second eradication. Eradication of H. pylori is now considered one of the first-line treatments for H. pylori-positive ITP, especially in Japan [3], and metronidazole was recommended as second-line therapy after failure of first-line eradication therapy in the Japanese guideline [4]. The duration of treatment will be shorter and less costly than immunosuppressive agents such as prednisolone, or trombopoietin receptor antagonists, and therefore less toxic in terms of long-term adverse effects. Although little is known about the efficacy of secondary eradication of residual H. pylori for ITP, it would be a useful treatment. Further investigation will be required.

Efficacy of a dose-intensified CHOP (Double-CHOP) regimen for peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of non-Hodgkin lymphomas, often resulting in poor prognoses. The CHOP chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine and prednisone, has been used previously to treat other types of lymphomas. Here, we examined the efficacy and safety of a dose-intensified CHOP regimen (Double-CHOP), which was followed by autologous stem-cell transplantation (ASCT) or high-dose methotrexate (HDMTX), in PTCL patients. Twenty-eight PTCL patients, who received 3 courses of Double-CHOP at our institution, were retrospectively studied from 1996 to 2012. Patients with anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+-ALCL) were excluded from this study. The median age of patients was 58 years (range: 17-69). They had low-intermediate (n=11), high-intermediate (n=10) or high (n=7) risk according to the International Prognostic Index (IPI). The overall complete remission (CR) rate following Double-CHOP treatment was 68%. Of the CR patients, 10 successfully tolerated a consolidated high-dose chemotherapy followed by ASCT and 7 received HDMTX. A single case of treatment-related mortality was recorded during the study. On a median 31-month follow-up, the estimated 3- or 5-year overall survival (OS) rates were 68 or 63%, respectively, while 3- or 5-year relapse-free survival (RFS) rates after CR were 60 or 43%, respectively. Although this study included elderly and excluded low-risk IPI and ALK+-ALCL patients, OS results were superiorly favourable, indicating the efficacy of this Double-CHOP regimen. However, an effective treatment strategy for refractory or relapsing patients needs to be validated and established.

Efficacy of oral cytarabine ocfosfate and etoposide in the treatment of elderly patients with higher-risk myelodysplastic syndromes compared to that in elderly acute myeloid leukemia patients.

Background: Elderly acute myeloid leukemia (AML) patients and patients with higher-risk myelodysplastic syndromes (MDS) have a much poorer prognosis than younger patients despite intensive chemotherapy. Methods: Ten patients with higher-risk MDS and 12 patients with AML over 65 years of age were enrolled into this study and received oral induction therapy with cytarabine ocfosfate and etoposide. Results: The therapy response rates were 60% in the MDS group and 41.7% in the AML group. The difference in overall survival among MDS and AML patients was not statistically significant. The difference in the median survival times of the responsive and nonresponsive groups, which included MDS and AML patients, was statistically significant (790 and 174 days, respectively). Conclusions: Based on a comparison of the data of this therapy in elderly higher-risk MDS patients versus elderly AML patients, we conclude that this therapy is well tolerated and can be cost-effective and useful for higher-risk MDS in elderly patients.

Mycotic pseudoaneurysm of a pulmonary artery branch caused by Cladosporium

We report the case of a 53‐year‐old male with a history of acute myelogenous leukemia, who suffered the rupturing of a right‐sided pulmonary artery pseudoaneurysm combined with pneumonia. He underwent a right‐sided lower lobectomy. The resected lung tissue demonstrated a mycotic pseudoaneurysm of a pulmonary artery branch together with a filamentous fungal infection. Pseudoaneurysms are caused by the breaching of all layers of a blood vessel wall. The extravasated blood is trapped by the surrounding extravascular tissue or clots. Cladosporium was detected during a polymerase chain reaction‐based analysis followed by DNA sequencing of formalin‐fixed paraffin‐embedded lung tissue samples. Although previous cases of pulmonary artery pseudoaneurysms caused by fungal infections, e.g., Candida or Aspergillus sp., have been reported, to the best of our knowledge this is the first case to involve cladosporiosis.

Enhanced perforin expression associated with dasatinib therapy in natural killer cells

We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy.

Clinical effect of immunophenotyping on the prognosis of multiple myeloma patients treated with bortezomib

In the present study, the effect of immunophenotyping on the prognoses of patients with multiple myeloma (MM) treated with bortezomib plus dexamethasone was investigated. The study involved 46 patients with MM, and analyzed the prognostic significance of the expression of cluster of differentiation (CD)45, CD56 and mature plasma cell (MPC)-1, and other factors including the International Staging System (ISS) stage, age, gender, the immunoglobulin subtype and the treatment line number prior to bortezomib treatment. Although CD56 and MPC-1 expression did not appear to affect the time to next treatment (TNT) or overall survival rate (OS), the univariate analysis determined that CD45 positivity was an adverse prognostic factor for TNT and OS, and that being male was significantly associated with inferior TNT and OS. Multivariate analyses determined that CD45 expression was prognostically significant for TNT and OS. In conclusion, CD45 positivity is an adverse prognostic factor in MM patients treated with bortezomib. The data from the present study demonstrate the clinical importance of classifying MM cells immunophenotypically to determine the prognoses of patients.