Yasunobu Sekiguchi

Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma

ALK-positive large B-cell lymphoma is a rare subtype of lymphoma, and most cases follow an aggressive clinical course with a poor prognosis. We examined an ALK-positive large B-cell lymphoma case showing an anti-ALK immunohistochemistry pattern distinct from those of 2 known ALK fusions, CLTC-ALK and NPM-ALK, for the presence of a novel ALK fusion; this led to the identification of SQSTM1-ALK. SQSTM1 is an ubiquitin binding protein that is associated with oxidative stress, cell signaling, and autophagy. We showed transforming activities of SQSTM1-ALK with a focus formation assay and an in vivo tumorigenicity assay using 3T3 fibroblasts infected with a recombinant retrovirus encoding SQSTM1-ALK. ALK-inhibitor therapies are promising for treating ALK-positive large B-cell lymphoma, especially for refractory cases. SQSTM1-ALK may be a rare fusion, but our data provide novel biological insights and serve as a key for the accurate diagnosis of this rare lymphoma.

Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma

A rapidly progressive motor-dominant neuropathy associated with IgM monoclonal antibody against gangliosides with disialosyl residues, GD3, GD1b, GT1b, and GQ1b, in a 60-year-old Japanese man with mantle cell lymphoma is reported. Plasma exchange and chemotherapy for mantle cell lymphoma were performed for the neuropathy and mantle cell lymphoma. After therapy, the motor neuropathy dramatically improved concurrently with substantial reduction of the antibody activities especially in reaction to GD1b. This is the first case report of neuropathy with anti-disialosyl IgM antibodies associated with mantle cell lymphoma, and plasma exchange and chemotherapy were effective.

Patient with Refractory Multiple Myeloma Developing Eosinophilia after Lenalidomide Treatment and Lung Cancer 9 Months Later: Case Report and Review of the Literature

Abstract A 78-year-old man was diagnosed as having advanced symptomatic IgG multiple myeloma in June 2008. Melphalan-prednisolone therapy was effective, however, relapse occurred in January 2011 after 21 courses of melphalan-prednisolone therapy. Addition of bortezomib and dexamethasone led to partial remission, but the treatment needed to be discontinued due to autonomic dysfunction. Combined therapy with lenalidomide and dexamethasone was started in May 2012, which resulted in partial remission. The patient had a persistently elevated eosinophil count (2,350/μL) and increased serum IL-6 level. Pleuritis carcinomatosa developed in January 2013. Lenalidomide was discontinued, which was followed by rapid improvement of the eosinophilia. The patient died of respiratory failure in March 2013. There have been only five reported cases of eosinophilia caused by lenalidomide used for the treatment of multiple myeloma. In these cases, lenalidomide has been speculated to activate cytotoxic T cells to control the plasmacytoma. It would be of interest, therefore, that eosinophilia could serve as a new indicator.

Angioimmunoblastic T-cell lymphoma with intramedullary production of platelet-derived growth factor and possibly complicating myelofibrosis: report of a case with review of the literature

A 65-year-old man was diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with bone marrow (BM) infiltration and myelofibrosis (MF). The BM infiltration and the condition of the MF improved following CHOP therapy (cyclophosphamide hydrate, doxorubicin hydrochloride, vincristine sulfate, and prednisolone). After complete remission was achieved, early central nervous system recurrence was noted, with no evidence of BM infiltration or MF. The lymph nodes and BM were examined for cytokines by immunohistochemical staining with monoclonal murine antibodies. The lymphoma cells were positive only for platelet-derived growth factor (PDGF) and negative for basic fibroblast growth factor, fibronectin, vascular endothelial growth factor, transforming growth factor-β (TGF-β), tumor necrosis factor α, interleukin-1β, and interleukin-6. It was thus inferred that the lymphoma cells producing PDGF caused the MF, and that the absence of MF at relapse may have been attributable to the absence of BM infiltration. There have been seven reported cases of AITL with intercurrent MF, although cytokine data (elevations of blood PDGF and TGFβ levels) are available for only one case. The present report is to our knowledge the only report of a case of AITL complicated by MF for which the results of immunohistostaining with anticytokine antibodies are available.

A case of T cell prolymphocytic leukemia involving blast transformation

We report a case of T cell prolymphocytic leukemia (T-PLL) involving blast transformation. At the initial diagnosis, most peripheral blood cells demonstrated proliferation of indolent T cell small cell variants, i.e., small to medium prolymphocytes with inconspicuous nucleoli and a normal karyotype. These cells were positive for surface CD4, CD5, and CD7, and cytoplasmic CD3, but negative for surface CD3 and CD8 and cytoplasmic terminal deoxynucleotidyl transferase (TdT). The T cell receptor (TCR) Cβ1 gene was rearranged in the cells. Large prolymphocytes with prominent nucleoli, irregular nuclei, and cytoplasmic vacuoles that exhibited chromosome 8 trisomy were observed about 1.5 years later. The CD4+CD8− single positive effector memory T cells transformed into surface CD4+CD8+ double positive precursor T cells. The clonal TCR gene rearrangement patterns of these cells were identical throughout the clinical course, suggesting clonal blast transformation. The CD4+CD8+ cells demonstrated increased chromosome 8 trisomy combined with complex chromosome abnormalities with t(14;14)(q11.2;q32) containing a 14q32 chromosome after transformation. T cell leukemia 1a (TCL1a) (14q32.1) may be implicated in this case. The TCL1a oncoprotein is expressed in approximately 70% of T-PLL cases. The disease gradually developed resistance to chemotherapy, and the patient died of the disease. It is known that indolent T-PLL can become aggressive. Therefore, similar transformations may occur in other aggressive T-PLL cases, particularly those involving trisomy 8 and TCL1a.

A Case of Advanced Primary Thyroid Double-Hit B Cell Lymphoma in Which Complete Remission has been Maintained After High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation Performed During the Second Remission, with a Review of the Literature.

A 50-year-old woman who presented with a mass in the thyroid gland was diagnosed as having diffuse large B-cell lymphoma (DLBCL) by biopsy in August 2011. The tumor had a complex chromosomal karyotype, including 8q24 (C-MYC) and 18q21(BCL-2), and fluorescence in situ hybridization confirmed split signals of C-MYC and BCL-2. BCL-2/IgH and C-MYC/IgH fusion signals were also observed. Three courses of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) therapy were given, followed by thyroid gland irradiation. She was achieved complete remission (CR). In January 2012, a mass appeared in the right breast, which was diagnosed as relapse by biopsy. CR was achieved again after the 4th course of R-CHOP therapy, and one course of rituximab, etoposide, methylprednisolone, cytarabine, cisplatin (R-ESHAP) therapy was given. Thereafter, CR has been maintained after high-dose chemotherapy and autologous peripheral blood stem cell transplantation. There have been only 3 reported cases of primary thyroid C-MYC and BCL-2 double-hit lymphoma, including the present case; 2 of the cases were cases of DLBCL. R-CHOP therapy, irradiation and autologous peripheral blood stem cell transplantation are expected to be effective for such patients.

Occurrence of Carcinoma of the Pancreas Following Nilotinib Therapy for Chronic Myeloid Leukemia: Report of a Case with Review of the Literature

The patient, a 79-year-old Japanese man, was diagnosed with the chronic phase of chronic myeloid leukemia and begun on nilotinib therapy in April 2011. The therapeutic response was major molecular response in August. About 19 months after the start of nilotinib therapy at 400 mg/day (November 2012), an adenocarcinoma (24x20 mm) confined to the head of the pancreas developed. In February 2013, a pancreaticoduodenectomy was performed. The therapy regimen was switched to dasatinib at 100 mg/day, beginning in April. The response was still major molecular response with no recurrence of pancreatic carcinoma in July 2013. There have been 29 reported cases of secondary neoplasms associated with nilotinib therapy. These secondary neoplasms were characterized by relatively frequent occurrence of papilloma (6 cases), gastric cancer (3 cases), fibroma (3 cases), and thyroid neoplasms (2 cases). The present case, however, is the first to be reported as carcinoma of the pancreas. This report describes the case.

Pleural effusion at diagnosis predicts extremely poor outcomes in patients with diffuse large B-cell lymphoma harbouring MYC rearrangement

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A case of Waldenstrom Macroglobulinemia in which intermittent one-day administration cycles of bendamustine were effective for alleviation of nausea and maintenance of remission

We have obtained consent from the patient for publication of this case report. The patient was a 73-year-old male. A routine medical checkup in 2008 revealed anemia and he was referred to our department. The laboratory findings at that time were as follows: hemoglobin (Hb), 8.8 g/dL; serum β2-microglobulin, 3.6 mg/mL; serum immunoglobulin M (IgM), 3880 mg/dL. Serum immunoelectrophoresis revealed a positive result for IgM-κ, and bone marrow examination showed an increase in small lymphocytes. The cell surface marker profile was as follows: IgM+, κ+, CD5+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+), FMC7+ and CD138-. Computed tomographic examination revealed no lymphadenopathy or hepatosplenomegaly. We diagnosed the patient with Waldenstrom Macroglobulinemia (WM). The patient was not tested for the myeloid differentiation factor 88 (MYD88) L256P mutation. The clinical course is shown in the figure. In 2009, the patient became transfusion-dependent, but had no systemic symptoms. In 2010, he developed systemic symptoms, and received treatment with R-COP (rituximab: 375 mg/m2, cyclophosphamide: 750 mg/ m2, vincristine: 1.5 mg/m2 and prednisolone: 100 mg for 5 days). This therapy proved ineffective, and the patient received bendamustine (120 mg/m2/day for 2 consecutive days) in 2011. With this treatment, the patient demonstrated partial response (PR).

CD4+CD8− T cell large granular lymphocytic leukaemia with central nervous system involvement

pipeline and an increasing number of new targets, clinical evaluation is likely to become rate-limiting. Approaches to overcome these challenges may be to enrich phase I ⁄ II trials with the molecular profile of tumours and to conduct integrated genomic profiling for specimens from patients enrolled in clinical trials. In addition, the development of robust predictive markers for response that are applicable in a routine clinical setting will be critical for this evaluation (Figure 1). The present findings further emphasize the importance of developing tools to relate findings from comprehensive biomarker studies to a standard clinical setting, which is still heavily dependent on evaluating FFPE specimens. In conclusion, we find that stratification based on high tumour cell content in fresh frozen tissue promotes selection of aggressive endometrial carcinomas. Thus, potential biomarkers identified need to be validated in population-based settings to determine their clinical relevance. Also, biomarkers that are only prevalent in subgroups with low tumour cell content may go unrecognized. The relevance of this phenomenon for other cancer types remains to be further investigated.