Kimihiro Kawakami

Association of Higher Methotrexate Dose With Lymphoproliferative Disease Onset in Rheumatoid Arthritis Patients

Methotrexate (MTX) is used as an anchor drug for rheumatoid arthritis (RA). Lymphoproliferative disease (LPD) occasionally develops in patients treated with MTX, and is known as MTX‐associated LPD (MTX‐LPD). Although MTX‐LPD occurs mainly in RA patients, it has not been established if MTX administration is an independent risk factor for LPD in RA patients. We examined the clinical characteristics of MTX‐LPD in Japanese RA patients and attempted to determine the risk factors for MTX‐LPD development.

Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)‐CML, patient data of D‐First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty‐two CML‐CP patients enrolled to this study were treated with dasatinib (100 mg day−1) and all were followed‐up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML‐CP. Am. J. Hematol. 90:819–824, 2015.

Establishment and characterization of a Kaposi's sarcoma- associated herpesvirus- and Epstein-Barr virus-negative malignant lymphoma cell line (OHK) with primary effusion lymphoma immunophenotype

Summary. A novel cell line, designated OHK, was established from ascites of a 59‐year‐old Japanese woman with diffuse large B‐cell lymphoma showing a peculiar serosal tropism, as seen in primary effusion lymphomas (PEL). OHK exhibited a large pleomorphic morphology with irregular nuclei and distinct nucleoli, and included immunoblastic and Reed–Sternberg‐like giant cells. On ultrastructural examination, rich intermediate filaments, and well‐developed Golgi apparati and rough endoplasmic reticulum, were seen. Immunophenotypically, OHK lacked T and B cell‐associated antigens, and had CD10, CD30, CD33 and CD138 antigens. Although OHK cells did not express immunoglobulin (Ig) protein, Southern blot analysis demonstrated clonal rearrangements of Ig heavy and light chain genes. These observations suggest that OHK cells are derived from preterminally differentiated B cells, and that they have features of PEL. Kaposis sarcoma‐associated herpesvirus and Epstein–Barr virus were not detected. OHK displayed hyperploid karyotypes with multiple structural abnormalities, and produced some cytokines such as macrophage‐colony‐stimulating factor (M‐CSF), granulocyte‐CSF, interleukin 6 and transforming growth factor β1. In particular, vascular endothelial growth factor (VEGF), whose stimulation of vascular permeability is thought to be critical to the pathogenesis of PEL, was also produced in large quantities. These results indicate that OHK may be a useful tool for the investigation of PEL.

A case of follicular lymphoma complicated with mesenteric panniculitis

Mesenteric panniculitis (MP) is a rare disease occasionally complicated with lymphoma. A 55-year old female presented with MP accompanied by malignant lymphoma. This patient was first treated for follicular lymphoma and subsequently for panniculitis. After 6 courses of R-CHOP chemotherapy, the treatment response was partial. An additional course of salvage chemotherapy led to a complete response. Since the mesenteric mass progressed simultaneously with the regression of other lymphoma lesions, we performed a biopsy of the mesenteric mass and pathologically confirmed an MP lesion without lymphoma. Subsequent high-dose chemotherapy led to CR and the MP lesion remained stable. In the present case, MP progressed with chemotherapy. We concluded that mesenteric lesions suspected of progressing or recurring should be diagnosed pathologically even if asymptomatic.

The Leading Seafood Cuisine of Anisakidosis in Japan

TO THE EDITOR—Iwata et al [1] reported the suitability and feasibility of freezing raw fish to eliminate the risk of anisakidosis infection. They compared frozen and raw sushi materials, squid, and mackerel, using a suitable scientific method. However, we discuss this study’s misleading interpretation. During the last few decades, many inexpensive sushi restaurants have opened in Japan, where people can enjoy affordable sushi cuisine. The growth of the sushi market has increased 1.5 times within the past decade. The gross market was worth 315 billion yen (

The inv(11)(p15q22) chromosome translocation of therapy-related myelodysplasia with NUP98-DDX10 and DDX10-NUP98 fusion transcripts

2.78 billion) in 2015. According to a nationwide survey, the incidence of anisakidosis (reported as food poisoning) has been rising in Japan (Figure 1) [2], which is discordant with the linear growth in the sushi market. The total frequency of the reported anisakidosis cases has raised 5 times much more than the growth ratio of sushi market in this decade. Therefore, we believe that the increase is due to a reporting bias (official reporting system recommended in 1999 and established in 2013). Some review articles have suggested that the increase in anisakidosis incidence is because of advances in endoscopic techniques and instruments [3, 4]. The substantial difference in anisakidosis prevalence between Japan and China, which has a culture of consuming raw seafood, is under investigation [3]. While Japanese eat fresh raw fish as sushi and sashimi, Chinese eat oil-cooked fish. This difference may be caused by different cooking styles in these countries. Based on the official record, the leading seafood source of anisakidosis is mackerel, of whichmore than half is pickled (Figure 1). Raw or undercooked squid is rarely the cause of food-related anisakidosis (Figure 1), indicating that squid is relatively safe. A comprehensive review on anisakidosis published in Clinical Infectious Disease revealed that seafood served in community sushi bars/restaurants tends to be less contaminated [5]. This may be because all franchised sushi restaurants in Japan use frozen squid. A higher incidence of anisakidosis is anticipated with the use of undercooked seafood in local food houses or homes [5].Epidemiological studies in Japan have revealed that anisakidosis is more frequent in coastal population, with most cases occurring among fishermen [5]. These factors suggest that the most unsafe cuisine in Japan is pickled mackerel. Pickling does not sterilize anisakids. Thus, the recommendations of Iwata et al will not help decrease the incidence of anisakidosis in Japan. We also have concerns on 2 minor issues. The first issue is that medical students and residents are not the most suitable participants to study because they are not the most typical representatives of the community. The second issue is regarding seafood freshness. The authors used seafood purchased unfrozen material 2 days earlier, which cannot be regarded as fresh. All franchised restaurant managers and sushi chefs have been educated to avoid the risk of anisakidosis. It is known that within 20 hours after the death of the host sea fish, anisakid larvae move from fish intestines to the muscles at 20°C but not at 4°C. Consumption of fresh unfrozen sushi without the risk of anisakidosis requires adequate preservation at 4°C and consumption on the day of the catch. In 2014, President Obama visited Japan formally and greatly enjoyed eating fresh seafood at the sushi dining bar Jiro in Ginza. Professionals know that really fresh sushi material, caught in the morning, has a minimal anisakidosis risk.